Archive for the ‘Genetic Testing’ Category

July 5, 2017 Credit: Cancer Research UK

Cancer patients should have routine access to genetic testing to improve diagnosis and treatment, according to England's chief medical officer.

Despite the UK being a world leader in genomic medicine its full potential is still not being realised, Professor Dame Sally Davies said in a new report.

Davies urged clinicians and the Government to work together and make wider use of new genetic techniques in an attempt to improve cancer survival rates.

Genetic testing can pinpoint the faults in DNA that have led to a cancer forming. Different cancers have different faults, and these determine which treatments may or may not work.

Such testing could lead to patients being diagnosed faster and receiving more targeted or precise treatments.

Davies said that "the age of precision medicine is now" and that the NHS must act quickly to remain world class.

"This technology has the potential to change medicine forever but we need all NHS staff, patients and the public to recognise and embrace its huge potential." said Davies.

Sir Harpal Kumar, Cancer Research UK's chief executive, agreed, saying that it would be a disservice to patients if the UK were slow to respond to innovations in this area.

The report recommends that within 5 years training should be available to current and future clinicians and that all patients should be being offered genomic tests just as readily as they're given MRI scans today.

Davies also called for research and international collaboration to be prioritised, along with investment in research and services so that patients across the country have equal access.

However the report recognises potential challenges such as data protection issues and attitudes of clinicians and the public.

"This timely report from the chief medical officer showcases just how much is now possible in genomics research and care within the NHS," added Sir Kumar.

"Cancer Research UK is determined to streamline research, to find the right clinical trial for cancer patients and to ensure laboratory discoveries benefit patients".

And the design of clinical trials are starting to change. A number of trials are underway, like Cancer Research UK's National Lung Matrix Trial with AstraZeneca and Pfizer, where patients with a certain type of lung cancer are assigned a specific treatment based on the genetic makeup of their cancer.

However, Sir Harpal Kumar stressed that to bring the report's vision to life the Government, the NHS, regulators and research funders need to act together.

Explore further: Adding abiraterone to standard treatment improves prostate cancer survival by 40 percent

Cancer Research UK is partnering with pharmaceutical companies AstraZeneca and Pfizer to create a pioneering clinical trial for patients with advanced lung cancer marking a new era of research into personalised medicines ...

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Greater access to genetic testing needed for cancer diagnosis and ... - Medical Xpress

Testing for abnormal breast cancer genes such as BRCA1, BRCA2, and PALB2 is usually done on a blood or saliva sample taken in your doctors office and sent to a commercial laboratory or a research testing facility. Most people have it done by a commercial lab. During testing, the genes are separated from the rest of the DNA, and then they are scanned for abnormalities.

Often, the type of genetic testing that's done and the specific genes being tested dictate whether testing in a research setting is possible. Research labs tend to perform free and anonymous testing. But they may provide limited results or require multiple family members to participate. In addition, test results may not be available for many months or years, and sometimes they're not available at all.

In the United States, several laboratories perform commercial BRCA1, BRCA2, and PALB2 testing, including Myriad Genetic Laboratories, Ambry Genetics, and GeneDx. They report results within 2 to 4 weeks. Abnormalities in other genes have also been associated with breast cancer risk. BRCA1 and BRCA2 mutations are the most common cause of hereditary breast cancer. Right now, PALB2 and other breast cancer gene abnormalities appear to be a less common cause of breast cancer, although testing for many of these genes is now also available. People choosing to undergo genetic testing may choose to be tested for only the BRCA1 and BRCA2 genes or to have multiple breast cancer-related genes tested together through a panel test. The cost of testing ranges from approximately $300 to $5,000, depending on whether you are being tested for only a specific area(s) of a gene known to be abnormal or if hundreds of areas are being examined within multiple genes.

Because different types of genetic abnormalities are detected by different test methodologies, it is important to be aware of the technical test type being performed. Gene sequencing detects the majority of genetic mutations. However, this test method cannot detect large mutations or genetic rearrangements that may occur within the genes. Therefore, testing the genes for large-scale mutations is also recommended. Most laboratories offering testing will perform both types of tests at the same time. If your testing was done in the past, it is possible screening for large-scale mutations was not performed. Inquire with the physician or genetic counselor who ordered testing to confirm what types of testing were completed and whether you may be eligible for any additional testing.

Find out if your insurance plan will cover genetic testing many insurance plans do. The 2008 Genetic Information Nondiscrimination Act (GINA) protects against discrimination by health insurance plans based on an individuals genetic information. However, if you're still concerned about your privacy, you may pay for the testing yourself and submit your blood sample under a code number or an assumed name. If you opt for the latter, choose a name you can remember easily and stick to it. In addition, GINA does not extend to life insurance, so securing life insurance coverage prior to genetic testing is suggested.

In 1988, the U.S. Congress passed the Clinical Laboratory Improvement Amendments (CLIA) to ensure quality standards and the accuracy and reliability of results across all testing laboratories (except research). Genetic testing should be performed by a CLIA-approved facility.

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Genetic Testing Facilities and Cost - Breastcancer.org

BBC News

Chief medical officer calls for gene testing revolution - BBC News BBC News Cancer patients should be routinely offered DNA tests to help select the best treatments for them, according to England's chief medical officer. Prof Dame Sally ... Gene testing could revolutionise cancer treatment - ITV NewsITV News Everything you need to know about the Government plan for genetic testing to treat cancer patientsBT.com Call for revolutionary DNA cancer care on NHSSky News Telegraph.co.uk -Daily Mail -Financial Times all 25 news articles »

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Chief medical officer calls for gene testing revolution - BBC News - BBC News

Cancer patients should have routine access to genetic testing to improve diagnosis and treatment, according to Englands chief medical officer.

Despite the UK being a world leader in genomic medicine its full potential is still not being realised, Professor Dame Sally Davies said in a new report.

This timely report from the chief medical officer showcases just how much is now possible in genomics research and care within the NHS. - Sir Harpal Kumar, Cancer Research UK

Davies urged clinicians and the Government to work together and make wider use of new genetic techniques in an attempt to improve cancer survival rates.

Genetic testing can pinpoint the faults in DNA that have led to a cancer forming. Different cancers have different faults, and these determine which treatments may or may not work.

Such testing could lead to patients being diagnosed faster and receiving more targeted or precise treatments.

Davies said that the age of precision medicine is now and that the NHS must act quickly to remain world class.

This technology has the potential to change medicine forever but we need all NHS staff, patients and the public to recognise and embrace its huge potential. said Davies.

Sir Harpal Kumar, Cancer Research UKs chief executive, agreed, saying that it would be a disservice to patients if the UK were slow to respond to innovations in this area.

The report recommends that within 5 years training should be available to current and future clinicians and that all patients should be being offered genomic tests just as readily as theyre given MRI scans today.

Davies also called for research and international collaboration to be prioritised, along with investment in research and services so that patients across the country have equal access.

However the report recognises potential challenges such as data protection issues and attitudes of clinicians and the public.

This timely report from the chief medical officer showcases just how much is now possible in genomics research and care within the NHS, added Sir Kumar.

Cancer Research UK is determined to streamline research, to find the right clinical trial for cancer patients and to ensure laboratory discoveries benefit patients.

And the design of clinical trials are starting to change. A number of trials are underway, like Cancer Research UKs National Lung Matrix Trial with AstraZeneca and Pfizer, where patients with a certain type of lung cancer are assigned a specific treatment based on the genetic makeup of their cancer.

However, Sir Harpal Kumar stressed that to bring the reports vision to life the Government, the NHS, regulators and research funders need to act together.

See original here:
Greater access to genetic testing needed for cancer diagnosis and treatment - Cancer Research UK

Ronan is the editor of Life Insurance International. You can reach him at ronan.mccaughey@verdict.co.uk

Would you share your genetic test results with a life or health insurer if it meant a cheaper policy in return?

Its an issue increasingly on the minds of insurers because access to genetic data would allow them to offer more personalised policies, potentially lower costs and assess policyholder risk much better.

And lets not forget, life and health insurers already have access to significant data on consumers medical history, as well as their lifestyle and activity patterns generated by wearable technology and fitness trackers.

Ross Campbell, life and health chief underwriter, research & development at Gen Re, recently wrote for Life Insurance International explaining that genomics, the field of molecular biology focused on mapping the genome, is at the forefront of a technological revolution in bio-medicine and healthcare.

So far, Campbell says the UK insurance industry has voluntarily agreed not to use much of the data that is available.

He explains that when introduced the moratorium acknowledged contemporary concerns that DNA sequencing would allow abnormal patterns in specific genes to be recognised and potentially misused by insurers.

Campbell says:

We now understand medical predictability can only rarely, such as Huntingtons Disease, be based on DNA alone, other risk factors may be more important as an example the combination effect of genes, nutrition, and exercise. But while exercise is linked with genetics, the relationship is too fragile for the results of direct-to-consumer genetic tests to be useful in making lifestyle recommendations.

He adds: Our collective understanding of genomics and its potential relevance to risk assessments has also improved significantly in recent years, and it offers the opportunity for insurers to do things better with individuals consent.

In October 2016 life reinsurer, Gen Re, said its survey of attitudes to genetic testing found that most people are open to being tested for genetic conditions, believing that it will help them to manage their health better.

Many indicated they would have a genetic test if it would give them a better understanding of any health risks they might face, mostly to allow early medical intervention.

Some wanted to understand what risks they might pass along to their children, while others would have a test if there was a good reason such as family history or existing illness.

Those who didnt want to be tested were reluctant about being burdened with knowledge about diseases about which they believe they could do nothing; they felt a test was unlikely to be useful in the absence of a clinical problem or history of genetic conditions in their relatives.

In the UK, at least, it is highly unlikely that life insurers will start using genetic data to set the level of cover anytime soon.

But rapid strides being made by the industry to digitalise and embrace data analytics means its not a question of if, but rather when, life and health insurers lobby the government and public to use genetic testing.

Decoding peoples DNA will be the next frontier for insurance.

More:
DNA insurance: Why genetic testing could revolutionise the industry - Verdict

The UK Governments chief medical adviser has unveiled plans where genome-based personalised medicine could open up for cancer patients within five years.

The genomics dream outlined by Professor Dame Sally Davies would see millions of patients having all their DNA tested as genome sequencing becomes as routine as MRI or CT scans.

Here is everything you need to know about the human genome and the proposed genetic testing to help treat cancer patients:

A genome is the genetic material of an organism.

In humans, it is made up of 23 chromosome pairs. Every persons genome contains 3.2 billion letters of genetic code, amounting to two terabytes of data.

Within the genome are 20,000 genes stretches of DNA that provide the software for making proteins.

Other parts of the genome act as dimmer switches regulating the activity of genes.

Having access to this genetic blueprint can make a huge difference to the diagnosis and treatment of someone with cancer or a rare disease.

In the case of cancer, tumour cells develop a different genome to normal cells. Comparing a patients normal and cancerous DNA can provide valuable clues about the best form of treatment.

However, this information is not set in stone. Cancers evolve rapidly and alter their DNA, which can make them resistant to treatments.

Genome testing at regular intervals can help clinicians keep up in the arms race with cancer and guide ongoing therapy.

It can also help distinguish between aggressive and deadly cancers and slow-growing tumours that may never threaten a patients life.

For adults and children with one of the 7,000 recognised rare diseases, genome testing could lead to far speedier and more effective treatment.

About 3.5 million individuals in the UK has a rare disease, many of them children under the age of five.

Currently having a rare disease identified involves multiple tests and several consultations.

The average patient sees five different doctors and is misdiagnosed three times before the nature of their illness is finally known. Reaching the end of this journey takes four years on average.

By reading a patients DNA rather than relying on the observation of often subtle symptoms, genomics testing can allow much faster diagnosis of rare diseases.

Currently, genetic testing of NHS patients in England is conducted through 25 regional laboratories and a plethora of smaller ones operating along the lines of a cottage industry, according to Dame Sally.

Her chief recommendation is to centralise all the labs and establish a national network providing equal access to the tests across the country.

Within government, a new national genomics board would be set up, chaired by a minister, to oversee the expansion and development of genomic services taking into account new advances within the rapidly evolving technology.

Her report calls for a simplified two-stage consent system and make it easier for patients to get involved in research studies and clinical trials.

Speaking at a news briefing in London, Dame Sally said she hoped to see the new system fully operational within five years.

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Everything you need to know about the Government plan for genetic testing to treat cancer patients - BreakingNews.ie

We are a society obsessed with information. Were constantly connected, click-click-clicking to access a steady stream of news, data, and social-media updates. Curiosity is a powerful motivator, but theres one area in which our thirst for knowledge has been inconsistent: genetic testing.

DNA tests have become du jour in the past decade. Technological advances and access to genomic testing translates into the ability to see whats beneath the hood of our chromosomal cars. Weve become obsessed with ancestry tests like 23andMe and finding out our babies sexes before theyre born, but we often shy away when it comes to more serious curiosities. Even though you can now easily find out if you carry the genetic mutations or changes for recessive diseases like spinal muscular atrophy, we often dont test for these genetic glitches because we just dont want to know. But its important that we find out.

Theres no doubt that genetics is complicated, and maybe its that lack of certainty that deters some people from diving into their DNA. Genetic disease can be confusing, with some mutations definitely resulting in disease and others leading only to increased risk. Some genetic diseases require that both parents have a mutation in order to stand a chance of having an affected child; others can be triggered by just one parent possessing a mutation. Its a bit of a crapshoot.

With so many diseases and conditions transmitted in different ways and identifiable at different stages of pregnancy, its no wonder that some women choose to forego prenatal testing at all; adopting a head-in-the-sand approach can be easier to cope with than grappling with the uncertainties raised by a DNA test.

But when it comes to prenatal testing, information is always a good thing. Knowing ahead of time about a condition can allow parents to set up a support network of family and friends and connect with other parents who have a child with a similar diagnosis. They can learn more about the condition with which their fetus has been diagnosed, seek out medical specialists ahead of time, and choose to deliver at a hospital that has the appropriate level of care for a baby with special needs.

Being surprised by an unexpected diagnosis on the day of delivery turns what should have been a joyous day into a day marked by confusion and fear.I interviewed scores of mothers for my book, The Gene Machine: How Genetic Technologies Are Changing the Way We Have KidsAnd the Kids We Have. In speaking with numerous women who didnt know while pregnant that they would give birth to children with special needs, Ive heard a common theme. Moms say that being surprised by an unexpected diagnosis on the day of delivery turned what should have been a joyous daythe birth of their childinto a day marked by confusion and fear. They wish they would have been aware of their childs diagnosis so that they could have come to terms with it before giving birth. That awareness could have allowed them to educate themselves and to prepare mentally and emotionally. It could have given them a jumpstart on processing and resolving the inevitable feelings of loss that come with learning that the baby youd hoped for is not the baby you have.

Pregnancy is not a perfect science; things can and do go awry. Worldwide, an astounding 8 million babies6% of birthsare born with a birth defect, many of which can be traced to genetics.

But even when the baby you give birth to may not be the perfect baby you expected, arming yourself with information ahead of time can make a big difference in how you process the experience of having a child with special needs. In 1987, Sesame Street writer Emily Perl Kingsley wrote about reconciling reality with expectations after the birth of her son, Jason, who was born in 1974 with Down syndrome.

When youre going to have a baby, its like planning a fabulous vacation trip to Italy. You buy a bunch of guidebooks and make wonderful plans. After months of eager anticipation, the day finally arrives. You pack your bags and off you go. Several hours later, the plane lands. The stewardess comes in and says, Welcome to Holland. Holland?!? you say. What do you mean Holland? I signed up for Italy! Im supposed to be in Italy. All my life Ive dreamed of going to Italy.

Some women decline genetic testing because they say that even if they receive a concerning diagnosis, they wouldnt alter the course of their pregnancy anyway. But thats rarely the case. As one genetic counselor told me, shes never had a couple do absolutely nothing upon learning that their fetus has a health issue. When people say they wouldnt do anything differently, she said, thats simply not true. Do anything differently is often code for abortion, yet ending a pregnancy is just one option upon receiving concerning genetic-test results. Many parents decide to continue an affected pregnancy.

Other women turn down the offer of genetic testing either because theyre overwhelmed by its complexity or because they mistakenly think theyre in the clear because they have no family history of genetic conditions. But family history, while useful, is a poor predictor of potential problems.

Consider autosomal recessive diseases such as cystic fibrosis, which affects one in 2,500 white babies. (Its less common in African American and Asian populations). If both parents carry the same genetic mutation, their children have only a 25% chance of developing the disease. Compare this with autosomal dominant mutations such as BRCA, often called the breast cancer gene. If either parent has a BRCA mutation, theres a 50% chance of passing that same genetic change to a child. Then there are conditions such as Down syndrome, which arent typically inherited and instead occur randomly around the time of conception.

Just because no one in your family suffers from a recessive disease doesnt mean youre not a carrier of it. Think back to those autosomal recessive diseases such as cystic fibrosis that occur only if both parents carry a mutation. Each pregnancy conceived by these carrier couples only has a 25% chance of developing the diseasethat means theres a 75% chance that any child will be disease-free. A mutation for one of these diseases could be unknowingly passed down for generations before two partners with the same mutation find one another and make a baby that has the unfortunate luck to inherit both problematic mutations.

We are no longer living in an era in which women have no choice but to remain in the dark about the health of their unborn children. All parents stand to benefit from knowing about potential problems ahead of time, which allows them to be proactive and take charge. Genetic testing before and during pregnancy can empower parents to make the decisions that are right for them, whether the itinerary of parenting leads them to Italy, Holland, or somewhere in between.

Learn how to write for Quartz Ideas. We welcome your comments at ideas@qz.com.

Originally posted here:
The real reason why all women should get their DNA tested - Quartz

Genetic testing involves examining your DNA, the chemical database that carries instructions for your body's functions. Genetic testing can reveal changes (mutations) in your genes that may cause illness or disease.

Although genetic testing can provide important information for diagnosing, treating and preventing illness, there are limitations. For example, if you're a healthy person, a positive result from genetic testing doesn't always mean you will develop a disease. On the other hand, in some situations, a negative result doesn't guarantee that you won't have a certain disorder.

Talking to your doctor, a medical geneticist or a genetic counselor about what you will do with the results is an important step in the process of genetic testing.

When genetic testing doesn't lead to a diagnosis but a genetic cause is still suspected, some facilities offer genome sequencing a process for analyzing a sample of DNA taken from your blood.

Everyone has a unique genome, made up of the DNA in all of a person's genes. This complex testing can help identify genetic variants that may relate to your health. This testing is usually limited to just looking at the protein-encoding parts of DNA called the exome.

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Genetic testing Overview - Mayo Clinic

Patients who underwent genetic screenings now fear that documentation of the results in their medical records could lead to problems if a new health law is enacted. Sam Edwards/Caiaimage/Getty Images hide caption

Patients who underwent genetic screenings now fear that documentation of the results in their medical records could lead to problems if a new health law is enacted.

Two years ago, Cheasanee Huette, a 20-year-old college student in Northern California, decided to find out if she was a carrier of the genetic mutation that gave rise to a disease that killed her mother. She took comfort in knowing that whatever the result, she'd be protected by the Affordable Care Act's guarantees of insurance coverage for pre-existing conditions.

Her results came back positive. Like her mother, she's a carrier of one of the mutations known as Lynch syndrome. The term refers to a cluster of mutations that can boost the risk of a wide range of cancers, particularly colon and rectal.

As Republican lawmakers advance proposals to overhaul the ACA's consumer protections, Huette frets that her future health coverage and employment options will be defined by that test.

She even wonders if documentation of the mutation in her medical records and related screenings could rule out individual insurance plans. She's currently covered under her father's policy. "Once I move to my own health care plan, I'm concerned about who is going to be willing to cover me, and how much will that cost," she says.

In recent years, doctors have urged patients to be screened for a variety of diseases and predisposition to illness, confident it would not affect their future insurability. Being predisposed to an illness such as carrying the BRCA gene mutations associated with breast and ovarian cancer does not mean a patient will come down with the illness. But knowing they could be at risk may allow patients to take steps to prevent its development.

Under the current health law, many screening tests for widespread conditions such as prediabetes are covered in full by insurance. The Centers for Disease Control and Prevention and the American Medical Association have urged primary care doctors to test patients at risk for prediabetes. But doctors, genetic counselors and patient advocacy groups now worry that people will shy away from testing as the ACA's future becomes more uncertain.

Dr. Kenneth Lin, a family physician at Georgetown University School of Medicine in Washington, D.C., says if the changes proposed by the GOP become law, "you can bet that I'll be even more reluctant to test patients or record the diagnosis of prediabetes in their charts." He thinks such a notation could mean hundreds of dollars a month more in premiums for individuals in some states under the new bill.

Huette says she's sharing her story publicly since her genetic mutation is already on her medical record.

But elsewhere, there have been "panicked expressions of concern," says Lisa Schlager of the patient advocacy group Facing Our Risk of Cancer Empowered (FORCE). "Somebody who had cancer even saying, 'I don't want my daughter to test now.' Or 'I'm going to be dropped from my insurance because I have the BRCA mutation.' There's a lot of fear."

Those fears, which come in an era of accelerating genetics-driven medicine, rest upon whether a gap that was closed by the ACA will be reopened. That remains unclear.

A law passed in 2008, the Genetic Information Nondiscrimination Act, bans health insurance discrimination if someone tests positive for a mutation. But that protection stops once the mutation causes "manifest disease" essentially, a diagnosable health condition.

That means "when you become symptomatic," although it's not clear how severe the symptoms must be to constitute having the disease, says Mark Rothstein, an attorney and bioethicist at the University of Louisville School of Medicine in Kentucky, who has written extensively about GINA.

The ACA, passed two years after GINA, closed that gap by barring health insurance discrimination based on pre-existing conditions, Rothstein says.

On paper, the legislation unveiled by Senate Majority Leader Mitch McConnell last week wouldn't let insurers set higher rates for people with pre-existing conditions, but it could effectively exclude such patients from coverage by allowing states to offer insurance plans that don't cover certain maladies, health analysts say. Meanwhile, the bill that passed the House last month does have a provision that allows states to waive protections for people with pre-existing conditions, if they have a gap in coverage of 63 days or longer in the prior year.

When members of a Lynch Syndrome social media group were asked for their views on genetic testing amid the current health care debate, about two dozen men and women responded. Nearly all said they were delaying action for themselves or suggesting that family members, particularly children, hold off.

Huette was the only one who agreed to speak for attribution. She says before the ACA was enacted, she witnessed the impact that fears about insurance coverage had on patients. Her mother, a veterinarian, had wanted to run her own practice but instead took a federal government job for the guarantee of health insurance. She died at the age of 57 of pancreatic cancer, one of six malignancies she had been diagnosed with over the years.

Huette says she doesn't regret getting tested. Without the result, Huette points out, how would she have persuaded a doctor to give her a colonoscopy in her 20s?

"Ultimately, my health is more important than my bank account," she says.

Kaiser Health News, a nonprofit health newsroom whose stories appear in news outlets nationwide, is an editorially independent part of the Kaiser Family Foundation.

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Patients Who Tested Positive For Genetic Mutations Fear Bias ... - NPR - NPR

Whole genome sequencing involves the analysis of all three billion pairs of letters in an individuals DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease.

However, the use of genome sequencing in healthy individuals is controversial because no one fully understands how many patients carry variants that put them at risk for rare genetic conditions and how theyand their doctorswill respond to learning about these risks.

Get more HMS news here

In a new paper published June 26 in the Annals of Internal Medicine by investigators at Harvard Medical School and Brigham and Womens Hospital, along with collaborators at Baylor College of Medicine, report the results of the four-year, NIH-funded MedSeq Project, the first-ever randomized trial conducted to examine the impact of whole genome sequencing in healthy primary care patients.

In the MedSeq Project, 100 healthy individuals and their primary care physicians were enrolled and randomized so that half of the patients received whole genome sequencing and half did not.

Nearly 5,000 genes associated with rare genetic conditions were expertly analyzed in each sequenced patient, and co-investigators from many different disciplines, including clinical genetics, molecular genetics, primary care, ethicsand law, were involved in analyzing the results.

Researchers found that among the 50 healthy primary care patients who were randomized to receive genome sequencing, 11 (22 percent) carried genetic variants predicted to cause previously undiagnosed rare disease.

Two of these patients were then noted to have signs or symptoms of the underlying conditions, including one patient who had variants causing an eye disease called fundus albipunctatus, which impairs night vision.

This patient knew he had difficulty seeing in low-light conditions but had not considered the possibility that his visual problems had a genetic cause.

Another patient was found to have a genetic variant associated with variegate porphyria, which finally explained the patients and family members mysterious rashes and sun sensitivity.

The other nine participants had no evidence of the genetic diseases for which they were predicted to be at risk. For example, two patients had variants that have been associated with heart rhythm abnormalities, but their cardiology workups were normal. It is possible, but not at all certain, that they could develop heart problems in the future.

Sequencing healthy individuals will inevitably reveal new findings for that individual, only some of which will have actual health implications, said lead author Jason Vassy,an HMS assistant professor of medicine at Brigham and Womens and primary care physician at the VA Boston Healthcare System.

This study provides some reassuring evidence that primary care providers can be trained to manage their patients sequencing results appropriately, and that patients who receive their results are not likely to experience anxiety connected to those results. Continued research on the outcomes of sequencing will be needed before the routine use of genome sequencing in the primary care of generally healthy adults can be medically justified, Vassy said.

Primary care physicians received six hours of training at the beginning of the study regarding how to interpret a specially designed, one-page genome testing report summarizing the laboratory analysis.

Consultation with genetic specialists was available, but not required. Primary care physicians then used their own judgment about what to do with the information, and researchers monitored the interactions for safety and tracked medical, behavioral and economic outcomes.

The researchers noted that they analyzed variants from nearly 5,000 genes associated with rare genetic diseases. These included single genes causing a significantly higher risk for rare disorders than the low-risk variants for common disorders reported by direct-to-consumer genetic testing companies. No prior study has ever examined healthy individuals for pathogenic (high-risk) variants in so many rare disease genes.

We were surprised to see how many ostensibly healthy individuals are carrying a risk variant for a rare genetic disease, said Heidi Rehm, HMS associate professor of pathology at Brigham and Women's anddirector of the Laboratory for Molecular Medicine at Brigham and Women's.

We found that about one-fifth of this sample population carried pathogenic variants, and this suggests that the potential burden of rare disease risk throughout our general population could be far higher than previously suspected,said Rehm, a co-investigator on the study who directed the genome analysis.However, the penetrance, or likelihood that persons carrying one of these variants will eventually develop the disease, is not fully known.

Additionally, investigators compared the two arms of the studyand found that patients who received genome sequencing results did not show higher levels of anxiety. They did, however, undergo a greater number of medical tests and incurred an average of $350 more in health care expenses in the six months following disclosure of their results. The economic differences were not statistically significant with the small sample size in this study.

Because participants in the MedSeq Project were randomized, we could carefully examine levels of anxiety or distress in those who received genetic risk information and compare it to those who did not, said Amy McGuire,director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine.

While many patients chose not to participate in the study out of concerns about what they might learn, or with fears of future insurance discrimination, those who did participate evinced no increase in distress, even when they learned they were carrying risk variants for untreatable conditions, saidMcGuire, who supervised the ethical and legal components of the MedSeq Project.

There has also been great concern in the medical community about whether primary care physicians can appropriately manage these complicated findings. But when a panel of expert geneticists reviewed how well the primary care physicians managed the patients with possible genetic risk variants, the experts determined that only two of the 11 cases were managed inappropriately and that no harm had come to these patients.

MedSeq Project investigators note that the studys findings should be interpreted with caution because of the small sample size and because the study was conducted at an academic medical center where neither the patients nor the primary care physicians are representative of the general population. They also stressed that carrying a genetic risk marker does not mean that patients have or will definitely get the disease in question. Critical questions remain about whether discovering such risk markers in healthy individuals will actually provide health benefits, or will generate unnecessary testing and subsequent procedures that could do more harm than good.

Integrating genome sequencing and other -omics technologies into the day-to-day practice of medicine is an extraordinarily exciting prospect with the potential to anticipate and prevent diseases throughout an individuals lifetime, said senior author Robert C. Green, HMSprofessor of medicineat Brigham and Womens Hospital,associate member of the Broad Institute of Harvard and MITandleader ofthe MedSeq Project. But we will need additionalrigorously designed and well-controlled outcomes studies like the MedSeq Project with larger sample sizes and with outcomes collected over longer periods of time to demonstrate the full potential of genomic medicine.

The MedSeq Project is one of the sites in the Clinical Sequencing Exploratory Research Consortium and was funded by the National Human Genome Research Institute, part of the National Institutes of Health.

The Genomes2People Research Program at Brigham and Womens Hospital, the Broad Institute and Harvard Medical School conducts empirical research in translational genomics and health outcomes. NIH-funded research within G2P seeks to understand the medical, behavioral and economic impact of using genetic risk information to inform future standards. The REVEAL Study has conducted several randomized clinical trials examining the impact of disclosing genetic risk for a frightening disease. The Impact of Personal Genomics (PGen) Study examined the impact of direct-to-consumer genetic testing on over 1,000 consumers of two different companies. The MedSeq Project has conducted the first randomized clinical trial to measure the impact of whole genome sequencing on the practice of medicine. The BabySeq Project is recruiting families of both healthy and sick newborns into a randomized clinical trial where half will have their babys genome sequenced. Green directs the Program.

Adapted from a Brigham and Women's news release.

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Genetic Testing for the Healthy - Harvard Medical School (registration)

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term variant rather than the term mutation to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.[1,2]

Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer.[1] These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling.[1,3] The PDQ cancer genetics information summaries on breast, ovarian, endometrial, colorectal, prostate, kidney, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.

The following are features that suggest hereditary cancer:

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:

It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition.[1] Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.

Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.

Several professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process. Examples of these organizations include the following:

A list of organizations that have published clinical practices guidelines related to genetic counseling, risk assessment, genetic testing, and/or management for hereditary breast and ovarian cancers is available in the PDQ summary on Genetics of Breast and Gynecologic Cancers.

Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information.[8,15] Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.

Genetic counseling has been defined by the American Society of Human Genetics as a communication process that deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family." The process involves an attempt by one or more appropriately trained persons to help the individual or family do the following:

In 2006, the National Society of Genetic Counselors further refined the definition of genetic counseling to include the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including integration of the following:

Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a familys culture and ethnicity; and other relevant background characteristics.[17,18] The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past.[19] Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information.[19] Findings from a psychosocial assessment can be used to help guide the direction of the counseling session.[9] An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for carriers of pathogenic variants and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[20] Uptake of genetic counseling services among those referred varies based on the cancer syndrome and the clinical setting. Efforts to decrease barriers to service utilization are ongoing (e.g., a patient navigator telephone call may increase utilization of these services).[21] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[22-27]

Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training.[28] Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional. The Cancer Genetics Services Directory provides a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services and is available on the National Cancer Institute's website.

The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported.[29-32] Despite these identified needs, the evidence indicates that competency in genetics and genomics remains limited across all health care disciplines, with the exception of genetic specialists.[33] Deficits in the following have been identified: (1) knowledge about hereditary cancer syndromes [34] and risk-appropriate management strategies;[35] (2) provision of genetic counseling services;[35] (3) documentation and use of personal and family cancer history to identify and refer patients at increased risk of hereditary cancer syndromes;[36-39] and (4) knowledge about genetic nondiscrimination laws.[36,40] (Refer to the table on Health Professional Practice and Genetic Education Information in the PDQ Cancer Genetics Overview summary for more information.)

The National Coalition for Health Professional Education in Genetics (whose work was transitioned to The Jackson Laboratory in 2013) has published core competencies for all health professionals. Building on this work, individual health professions, such as physicians,[32] nurses,[41,42] physician assistants,[43] pharmacists,[44] and genetic counselors,[45] have developed and published core competencies specific to their profession. A number of other organizations have also published professional guidelines, scopes, and standards of practice.

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies are being explored, including group sessions, telephone counseling, and telemedicine by videoconferencing.[46-53] Additionally, computer programs and websites designed to provide genetics education can be successful adjuncts to personal genetic counseling services in a computer-literate population.[54-58]

Some studies of patient satisfaction with cancer genetic counseling services have been published. For example, one survey of individuals who participated in a cancer genetics program in its inaugural year reported that the clinical services met the needs and expectations of most people.[59] Patients reported that the best parts of the experience were simply having a chance to talk to someone about cancer concerns, having personalized summary letters and family pedigrees, learning that cancer risk was lower than expected, or realizing that one had been justified in suspecting the inheritance of cancer in ones family.

Several studies have since shown that the majority of individuals are satisfied with their genetic counseling experience.[60-63] However, one study of 61 women participating in a BRCA1/2 genetic testing program found that satisfaction with genetic counseling was influenced by psychological variables including optimism, family functioning, and general and cancer-specific distress.[64]

A meta-analysis of several controlled studies showed that outcomes of genetic counseling included improvement in cancer genetic knowledge (pooled short-term difference, 0.70 U; 95% confidence interval, 0.151.26 U). Overall, no long-term increases in general anxiety, cancer-specific worry, distress, or depression were detected as a consequence of genetic counseling. However, the impact of genetic counseling on risk perception is less clear, with some studies reporting no change in risk perception while others report significant differences before and after counseling.[65]

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available.[1-4] Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status. In some cases, referral for psychotherapeutic treatment may be recommended prior to, or in lieu of, testing.[5]

Concepts of personal cancer risk, genetics, and the relationship between the two can be complex and can be difficult for patients to understand. A number of factors influence a persons concept of his or her risk, which may not be congruent with evidence-based quantitative calculations. These factors include:

A thorough understanding of these issues can greatly inform genetic education and counseling. These factors influence the processing of risk information and subsequent health behaviors.[9]

The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individuals knowledge, beliefs, emotions, and behaviors associated with risk and the risk message conveyed. Accordingly, the goal of risk communication may be to impact the individuals knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.

Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members, and the media.[10] This information may be more salient or emotional if a family member has recently died from cancer or if there is a new family diagnosis.[11,12] Additionally, individuals may have beliefs about how genetic susceptibility works in their family.[13,14] For example, in a family where only females have been affected with an autosomal dominant cancer susceptibility syndrome thus far, it may be difficult to convince the consultand that her sons have a 50% risk of inheriting the disease-related pathogenic variant. The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals receptivity to the cancer risk communication process and also represent the context in which individuals will return to continue ongoing decision making about how to manage their risk.[15,16] As such, individuals beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.

Perceived risk can play an important role in an individuals decision to participate in counseling,[17] despite the fact that perceived risk often varies substantially from statistical risk estimates.[18-20]

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:

For consultands with a history of cancer, additional information collected includes the following:

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information in a study that utilized a sample (N = 104) that varied widely in educational attainment.[22] A nine-question family history screening tool has been shown to identify individuals at increased risk of common health conditions, including cancer, who warrant a more detailed family history (receiver operating characteristic, 84.6% [range, 81.2%88.1%]; sensitivity, 95% [range, 92%98%]; specificity, 54% [range, 48%60%]).[23] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [24] and that the use of these questionnaires is an acceptable and understandable family history collection method.[25] However, questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[26] Routine chart reviews (e.g., via electronic medical records) may be worthwhile to maximize the identification of appropriate candidates for genetic counseling referral. In a single nonacademic institution, systematic chart review by a genetic counselor increased the number of referrals for genetics consultation.[27] The most significant improvement was in ovarian cancer referrals. In conjunction with other efforts to collect and review family history, the performance of routine chart reviews may help identify gaps in existing referral patterns. Additionally, collecting family history from multiple relatives in a single family has been shown to increase the number of reported family members with cancer, compared with family history information provided by a single family member.[28]

Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[29,30] Factors suggesting inherited cancer risk in a family are described below.

Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. In the United States, many are written at reading grade levels above 8th grade, which may reduce their effectiveness in gathering accurate family history information. On average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[31]

Standards of pedigree nomenclature have been established.[29,30] Refer to Figure 1 for common pedigree symbols.

Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.

Documentation of a family cancer history typically includes the following:

A three-generation family history includes the following:

For any relative with cancer, collect the following information:[33]

For relatives not affected with cancer, collect the following information:

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[34] However, people often have incomplete or inaccurate information about the cancer history in their family.[30,33,35-41] Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations.[42] Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.[37,43]

A population-based survey of 2,605 first- and second-degree relatives confirmed proband reports of cancer diagnoses and found that the accuracy of reported cancer diagnoses in relatives was low to moderate, while reports of no history of cancer were accurate.[39] Accuracy varies by cancer site and degree of relatedness.[39,44,45] Reporting of cancer family histories may be most accurate for breast cancer [39,45] and less accurate for gynecologic malignancies [39,45] and colon cancer.[39] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[37,43,45] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates. A U.K. study illustrates the importance of verification of the cancer family history in individuals with a family history of breast cancer (n = 2,278) and colon cancer (n = 1,184).[41] Changes in genetic risk assignment (reassignment) from baseline to final time points (e.g., low risk to high risk) warranting management changes were reported in nearly 30% of families with colorectal cancer and 20% of families with breast cancer. Verification of reported cancer diagnoses in this cohort revealed a lower overall degree of consistency between reported and confirmed diagnoses than in other studies.[37,46]

It is also important to consider limited, missing, or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions. When there are few family members of the at-risk gender when considering a particular syndrome with primarily male or female specific disease manifestations, the family history may be difficult to assess (e.g., few female members in a family at risk of hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family.[47] Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.

Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. Furthermore, changes in the cancer family history over time may alter recommendations for earlier or more intense cancer screening. A descriptive study that examined baseline and follow-up family history data from a U.S. population-based cancer registry reported that family history of breast cancer or colorectal cancer becomes increasingly relevant in early adulthood and changes significantly from age 30 years to age 50 years.[48] Therefore, it is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.

Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced by the consultand in the process of gathering family history information.

After an individuals personal and family cancer histories have been collected, several factors could warrant referral to a genetics professional for evaluation of hereditary cancer susceptibility syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal and family history criteria to guide the identification of at-risk individuals and appropriate referral for cancer genetic risk consultation.[49] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:

The following sections relate to the way that each of these questions might be addressed:

The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:

Clinical characteristics associated with distinctive risk ranges for different cancer genetic syndromes are summarized in the second edition of the Concise Handbook of Familial Cancer Susceptibility Syndromes.[50]

Hundreds of inherited conditions are associated with an increased risk of cancer. These have been summarized in texts [51-53] and a concise review.[50] Diagnostic criteria for different hereditary syndromes incorporate different features from the list above, depending on the original purpose of defining the syndrome (e.g., for gene mapping, genotype -phenotype studies, epidemiological investigations, population screening, or clinical service). Thus, a syndrome such as Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]) can be defined for research purposes by the Amsterdam criteria as having three related individuals with colorectal cancer, with one person being a first-degree relative of the other two; spanning two generations; and including one person who was younger than age 50 years at cancer diagnosis, better known as the 3-2-1 rule. These criteria have limitations in the clinical setting, however, in that they ignore endometrial and other extracolonic tumors known to be important features of Lynch syndrome. Revised published criteria that consider extracolonic cancers of Lynch syndrome have been subsequently developed and include the Amsterdam criteria II and the revised Bethesda guidelines.

Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology. These factors include the following:

The mode of inheritance refers to the way that genetic traits are transmitted in the family. Mendels laws of inheritance posit that genetic factors are transmitted from parents to offspring as discrete units known as genes that are inherited independently from each other and are passed on from an older generation to the following generation. The most common forms of Mendelian inheritance are autosomal dominant, autosomal recessive, and X-linked. Non-Mendelian forms of inheritance include chromosomal, complex, and mitochondrial. Researchers have learned from cancer and other inherited diseases that even Mendelian inheritance is modified by environmental and other genetic factors and that there are variations in the ways that the laws of inheritance work.[54-56]

Most commonly, Mendelian inheritance is established by a combination of clinical diagnosis with a compatible, but not in itself conclusive, pedigree pattern.[57] Below is a list of inheritance patterns with clues to their recognition in the pedigree, followed by a list of situations that may complicate pedigree interpretation.

Autosomal dominant

Autosomal recessive

X-linked

Chromosomal

Complex

Susceptibility or resistance shows a more or less normal distribution in the population. Most people have an intermediate susceptibility, with those at the tails of the distribution curve having unusually low or unusually high susceptibility. Affected individuals are presumably those who are past a point of threshold for being affected due to their particular combination of risk factors. Outside of the few known Mendelian syndromes that predispose to a high incidence of specific cancer, most cancers are complex in etiology.

Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to pathogenic variants in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[58]

The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although pathogenic variants in major cancer susceptibility genes lead to recognizable Mendelian inheritance patterns, they are uncommon. Nonetheless, cancer susceptibility genes are estimated to contribute to the occurrence of organ-specific cancers from less than 1% to up to 15%.[59] Pathogenic variants in these genes confer high relative risk and high absolute risk. The attributable risk is low, however, because they are so rare.

In contrast, scientists now know of polymorphisms or alterations in deoxyribonucleic acid that are very common in the general population. Each polymorphism may confer low relative and absolute risks, but collectively they may account for high attributable risk because they are so common. Development of clinically significant disease in the presence of certain genetic polymorphisms may be highly dependent on environmental exposure to a potent carcinogen. People carrying polymorphisms associated with weak disease susceptibility may constitute a target group for whom avoidance of carcinogen exposure may be highly useful in preventing full-blown disease from occurring.

For more information about specific low-penetrance genes, please refer to the summaries on genetics of specific types of cancer.

Complex inheritance might be considered in a pedigree showing the following:

These probabilities vary by syndrome, family, gene, and pathogenic variant, with different variants in the same gene sometimes conferring different cancer risks, or the same variant being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity discussed elsewhere.

A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[60] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, Mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.[60]

The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a pathogenic variant.[61] Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendels laws, Bayesian analysis, and specific health information, such as tumor-specific features.[61,62] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.

If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models website or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and pathogenic variant probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominately female in origin, adoption, and early deaths from other causes.[62,63] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[64] In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[61,62,64]

When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[1,65] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.

Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individuals personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable).[66] Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).

Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data.[1] Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant's effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA pathogenic variant).[67] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.[1]

In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[65] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[65,68]

In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[65,68] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[62] Furthermore, many of these models were constructed from data derived from predominately Caucasian populations and may have limited validity when used to estimate risk in other ethnicities.[69]

Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[70,71] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.

In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[61] Influencing factors include the following:

A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[72] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[61]

Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Current recommendations are summarized in the PDQ summaries addressing the genetics of specific cancers.

The goal of genetic education and counseling is to help individuals understand their personal risk status, their options for cancer risk management, and to explore feelings regarding their personal risk status. Counseling focuses on obtaining and giving information, promoting autonomous decision making, and facilitating informed consent if genetic testing is pursued.

Optimally, education and counseling about cancer risk includes providing the following information:

When a clinically valid genetic test is available, education and counseling for genetic testing typically includes the following:

If a second session is held to disclose and interpret genetic test results, education and counseling focuses on the following:

The process of counseling may require more than one visit to address medical, genetic testing, and psychosocial support issues. Additional case-related preparation time is spent before and after the consultation sessions to obtain and review medical records, complete case documentation, seek information about differential diagnoses, identify appropriate laboratories for genetic tests, find patient support groups, research resources, and communicate with or refer to other specialists.[1]

Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the health care provider periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new genetic testing or treatment options are available is controversial, and standards have not been established.

The usage of numerical probabilities to communicate risk may overestimate the level of risk certainty, especially when wide confidence intervals exist to the estimates or when the individual may differ in important ways from the sample on which the risk estimate was derived. Also, numbers are often inadequate for expressing gut-level or emotional aspects of risk. Finally, there are wide variations in individuals level of understanding of mathematical concepts (i.e., numeracy). For all the above reasons, conveying risk in multiple ways, both numerically and verbally, with discussion of important caveats, may be a useful strategy to increase risk comprehension. The numerical format that facilitates the best understanding is natural frequencies because frequencies include information concerning the denominator, the reference group to which the individual may refer. In general, logarithmic scales are to be avoided.[2] Additionally, important contextual risks may be included with the frequency in order to increase risk comprehension; these may include how the persons risk compares with those who do not have the risk factor in question and the risks associated with common hazards, such as being in a car accident. Additional suggestions include being consistent in risk formats (do not mix odds and percentages), using the same denominator across risk estimates, avoiding decimal points, including base rate information, and providing more explanation if the risk is less than 1%.

The communication of risk may be numerical, verbal, or visual. Use of multiple strategies may increase comprehension and retention of cancer genetic risk information.[2] Recently, use of visual risk communication strategies has increased (e.g., histograms, pie charts, and Venn diagrams). Visual depictions of risk may be very useful in avoiding problems with comprehension of numbers, but research that confirms this is lacking.[3,4] A study published in 2008 examined the use of two different visual aids to communicate breast cancer risk. Women at an increased risk of breast cancer were randomized to receive feedback via a bar graph alone or a bar graph plus a frequency diagram (i.e., highlighted human figures). Results indicate that overall, there were no differences in improved accuracy of risk perception between the two groups, but among those women who inaccurately perceived very high risk at baseline, the group receiving both visual aids showed greater improvement in accuracy.[5]

The purpose of risk counseling is to provide individuals with accurate information about their risk, help them understand and interpret their risk, assist them as they use this information to make important health care decisions, and help them make the best possible adjustment to their situation. A systematic review of 28 studies that evaluated communication interventions showed that risk communication benefits users cognitively by increasing their knowledge and understanding of risk perception and does not negatively influence affect (anxiety, cancer-related worry, and depression). Risk communication does not appear to result in a change in use of screening practices and tests. Users received the most benefit from an approach utilizing risk communication along with genetic counseling.[6,7] Perceptions of risk are affected by the manner in which risk information is presented, difficulty understanding probability and heredity,[8,9] and other psychological processes on the part of individuals and providers.[10] Risk may be communicated in many ways (e.g., with numbers, words, or graphics; alone or in relation to other risks; as the probability of having an adverse event; in relative or absolute terms; and through combinations of these methods). The way in which risk information is communicated may affect the individuals perception of the magnitude of that risk. In general, relative risk estimates (e.g., "You have a threefold increased risk of colorectal cancer") are perceived as less informative than absolute risk (e.g., "You have a 25% risk of colorectal cancer") [11] or risk information presented as a ratio (e.g., 1 in 4).[9] A strong preference for having BRCA1/2 pathogenic variant risk estimates expressed numerically is reported by women considering testing.[12] Individuals associate widely differing quantitative risks with qualitative descriptors of risk such as rare or common.[13] More research is needed on the best methods of communicating risk in order to help individuals develop an accurate understanding of their cancer risks.

Recent descriptive examination of the process of cancer genetic counseling has found that counseling sessions are predominantly focused on the biomedical teaching required to inform clients of their choices and to put genetic findings in perspective but that attention to psychosocial issues does not detract from teaching goals and may enhance satisfaction in clients undergoing counseling. For instance, one study of communication patterns in 167 pretest counseling sessions for BRCA1 found the sessions to have a predominantly biomedical and educational focus;[14] however, this approach was client focused, with the counselor and client contributing equally to the dialogue. These authors note that there was a marked diversity in counselor styles, both between counselors and within different sessions, for each counselor. The finding of a didactic style was corroborated by other researchers who examined observer-rated content checklists and videotape of 51 counseling sessions for breast cancer susceptibility.[15] Of note, genetic counselors seemed to rely on demographic information and breast cancer history to tailor genetic counseling sessions rather than clients self-reported expectations or psychosocial factors.[16] Concurrent provision of psychosocial and scientific information may be important in reducing worry in the context of counseling about cancer genetics topics.[17] An increasing appreciation of language choices may contribute to enhanced understanding and reduced anxiety levels in the session; for example, it was noted that patients may appreciate synonymic choices for the word mutation, such as altered gene.[18] Some authors have published recommendations for cultural tailoring of educational materials for the African-American population, such as a large flip chart, including the use of simple language and pictures, culturally identifiable images (e.g., spiritual symbols and tribal patterns), bright colors, and humor.[19]

Studies have examined novel channels to communicate genetic cancer risk information, deliver psychosocial support, and standardize the genetic counseling process for individuals at increased risk of cancer.[20-27] Much of this literature has attempted to make the genetic counseling session more efficient or to limit the need for the counselor to address basic genetic principles in the session to free up time for the clients personal and emotional concerns about his or her risk. For example, the receipt of genetic feedback for BRCA1/2 and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated.[28] Other modalities include the development of patient assessments or checklists, CD-ROM programs, and interactive computer programs.

Patient assessments or checklists have been developed to facilitate coverage of important areas in the counseling session. One study assessed patients psychosocial needs before a hereditary cancer counseling session to determine the assessments effect on the session.[29] A total of 246 participants from two familial cancer clinics were randomly assigned to either an intervention arm in which the counselor received assessment results or a usual care control arm. Study results demonstrated that psychosocial concerns were discussed more frequently among intervention participants than among controls, without affecting session length. Moreover, cancer worry and psychological distress were significantly lower for intervention versus control participants 4 weeks after the counseling session.

A second study compared a feedback checklist completed by 197 women attending a high-risk breast clinic prior to the counseling session to convey prior genetic knowledge and misconceptions to aid the counselor in tailoring the session for that client.[22] The use of the feedback checklist led to gains in knowledge from the counseling session but did not reduce genetic counseling time, perhaps because the genetic counselor chose to spend time discussing topics such as psychosocial issues. Use of the checklist did decrease the time spent with the medical oncologist, however. The feedback checklist was compared to a CD-ROM that outlined basic genetic concepts and the benefits and limitations of testing and found that those viewing the CD-ROM spent less time with counselors and were less likely to choose to undergo genetic testing. The CD-ROM did not lead to increased knowledge of genetic concepts, as did use of the checklist.

A prospective study evaluated the effects of a CD-ROM decisional support aid for microsatellite instability (MSI) tumor testing in 239 colorectal cancer patients who met the revised Bethesda criteria but who did not meet the Amsterdam criteria.[30] The study also tested a theoretical model of factors influencing decisional conflict surrounding decisions to pursue MSI tumor testing. Within the study, half of the sample was randomly assigned to receive a brief description of MSI testing within the clinical encounter, and the other half was provided the CD-ROM decisional support aid in addition to the brief description. The CD-ROM and brief description intervention increased knowledge about MSI testing more than the brief description alone did. As a result, decisional conflict decreased because participants felt more prepared to make a decision about the test and had increased perceived benefits of MSI testing.

Other innovative strategies include educational materials and interactive computer technology. In one study, a 13-page color communication aid using a diverse format for conveying risk, including graphic representations and verbal descriptions, was developed.[23] The authors evaluated the influence of the communication aid in 27 women at high risk of a BRCA1/2 pathogenic variant and compared those who had read the aid to a comparison sample of 107 women who received standard genetic counseling. Improvements in genetic knowledge and accuracy of risk perception were documented in those who had read the aid, with no differences in anxiety or depression between groups. Personalized, interactive electronic materials have also been developed to aid in genetic education and counseling.[24,25] In one study, an interactive computer education program available prior to the genetic counseling session was compared with genetic counseling alone in women undergoing counseling for BRCA1/2 testing.[25] Use of the computer program prior to genetic counseling reduced face-time with the genetic counselor, particularly for those at lower risk of a BRCA1/2 pathogenic variant. Many of the counselors reported that their clients use of the computer program allowed them to be more efficient and to reallocate time spent in the sessions to clients unique concerns.

Videoconferencing is an innovative strategy to facilitate genetic counseling sessions with clients who cannot travel to specialized clinic settings. In 37 individuals in the United Kingdom, real-time video conferencing was compared with face-to-face counseling sessions; both methods were found to improve knowledge and reduce anxiety levels.[26] Similarly, teleconferencing sessions, in which the client and genetic specialists were able to talk with each other in real time, were used in rural Maine communities [27] in the pediatric context to convey genetic information and findings for developmental delays and were found to be comparable to in-person consultations in terms of decision-making confidence and satisfaction with the consultations. An Australian study compared the experiences of 106 women who received hereditary breast and ovarian cancer genetic counseling via videoconferencing with the experiences of 89 women who received counseling face to face. Pre- and 1-month postcounseling assessments revealed no significant differences in knowledge gains, satisfaction, cancer-specific anxiety, generalized anxiety, depression, and perceived empathy of the genetic counselor.[31]

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Cancer Genetics Risk Assessment and Counseling (PDQ ...

Genetic testing can help estimate your chance of developing cancer in your lifetime. It does this by searching for specific changes in your genes, chromosomes, or proteins. These changes are called mutations.

Genetic tests are available for breast, ovarian, colon, thyroid, and some other cancers. Genetic testing may help:

Predict your risk of a particular disease

Find if you have genes that may pass increased cancer risk to your children

Manage increased cancer risk by having more regular cancer screening or taking steps to lower risk

No genetic test can say you will, certainly, develop cancer. However, a test can tell you if you have a higher risk of developing cancer than most people.

Only some people with a gene mutation will develop cancer. For example, a woman with a 75% chance of breast cancer may never develop the disease. Meanwhile, a woman with a 25% chance may develop breast cancer.

A hereditary cancer is any cancer caused by a gene mutation. The following factors suggest that a person may be at risk:

Family history of cancer. Having 3 or more relatives on the same side of the family with the same or related forms of cancer

Cancer at an early age. Having 2 or more relatives diagnosed with cancer at an early age, which may be different depending on the type of cancer

Multiple cancers. Having 2 or more types of cancer occurring in the same relative

Genetic testing is a personal decision made for various reasons. And its a complex decision best made in collaboration. Engage your family, doctor, and genetic counselor in the process.

ASCO recommends considering genetic testing in the following cases:

You have a personal or family history that suggests a genetic cause of cancer

The test can clearly show a specific genetic change

Results help with diagnosis or management of the genetic condition or cancer(s).For example, you may choose steps to lower your risk. Steps may include surgery, medication, frequent screening, or lifestyle changes.

In addition, ASCO recommends genetic counseling before and after genetic testing. Learn more about ASCO's latest recommendations on genetic testing for cancer susceptibility.

Genetic testing has limitations and emotional implications.

Depression, anxiety, or guilt. A positive test result means a gene mutation exists. This result may bring difficult emotions. Some people may think of themselves as sick, even if they never develop cancer. Others may experience guilt if family members have a mutation but they dont.

Family tension. A person may feel responsible for telling family members about test results. This information may complicate family dynamics. Learn more about sharing genetic test results with your family.

A false sense of security. A negative result means that a person doesnt have a specific genetic mutation. However, a person with a negative result may still develop cancer. A negative result only means the persons risk is average. Additionally, each persons risk is affected by lifestyle, environmental factors, and medical history.

Unclear results. A gene may have a mutation not linked with cancer risk. This is called a variant of unknown significance. It means its unclear whether the mutation will increase risk. Or, a person may have a mutation that current tests cannot detect. Many cancers are not yet tied to a specific gene. Moreover, some genes may interact unpredictably with other genes or environmental factors. And these interactions may cause cancer. Thus, it may be impossible to calculate the cancer risk.

High cost. Genetic testing can be expensive. Its particularly expensive if insurance doesnt pay for it.

Discrimination and privacy concerns. Some people fear genetic discrimination from test results. Others worry about the privacy of their genetic information. The Genetic Information Nondiscrimination Act (GINA) protects against employment or health coverage discrimination based on genetic information. Discuss concerns about potential employment, health, or life insurance discrimination with a genetic counselor or doctor.

Before undergoing genetic testing, learn about its risks and limitations. Identify your reasons for wanting a test. And consider how you will cope with test results.

Here are some questions to help you make a decision:

Do Ihave a family history of cancer?

Have Ideveloped cancer at an earlier-than-average age?

Howwill I interpret the results of genetic testing? Who will help me use thisinformation?

Willthe test results affect my medical care or the medical care of my family?

If Ihave a genetic condition, can I lower my cancer risk?

A genetic counselor can help address these questions. This professional is trained to advise about genetic testings risks and benefits. A genetic counselor also helps people through the genetic testing process. Learn more about what to expect when meeting with a genetic counselor.

Understanding Cancer Risk

The Genetics of Cancer

Understanding Statistics Used to Estimate Risk and Recommend Screening

National Human Genome Research Institute: Issues in Genetics

See the original post:
Genetic Testing for Cancer Risk | Cancer.Net

This article is about genetic tests for disease and ancestry or biological relationships. For use in forensics, see DNA profiling.

Genetic testing, also known as DNA testing, allows the the determination of bloodlines and the genetic diagnosis of vulnerabilities to inherited diseases. In agriculture, a form of genetic testing known as progeny testing can be used to evaluate the quality of breeding stock. In population ecology, genetic testing can be used to track genetic strengths and vulnerabilities of species populations.

In humans, genetic testing can be used to determine a child's parentage (genetic mother and father) or in general a person's ancestry or biological relationship between people. In addition to studying chromosomes to the level of individual genes, genetic testing in a broader sense includes biochemical tests for the possible presence of genetic diseases, or mutant forms of genes associated with increased risk of developing genetic disorders.

Genetic testing identifies changes in chromosomes, genes, or proteins.[1] The variety of genetic tests has expanded throughout the years. In the past, the main genetic tests searched for abnormal chromosome numbers and mutations that lead to rare, inherited disorders. Today, tests involve analyzing multiple genes to determine the risk of developing certain more common diseases such as heart disease and cancer.[2] The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person's chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed.[3][4]

Because genetic mutations can directly affect the structure of the proteins they code for, testing for specific genetic diseases can also be accomplished by looking at those proteins or their metabolites, or looking at stained or fluorescent chromosomes under a microscope.[5]

Genetic testing is "the analysis of chromosomes (DNA), proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes."[6] It can provide information about a person's genes and chromosomes throughout life. Available types of testing include:

Non-diagnostic testing includes:

Many diseases have a genetic component with tests already available.

over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence[15]

Obstructive lung disease in adults; liver cirrhosis during childhood; when a newborn or infant has jaundice that lasts for an extended period of time (more than a week or two), an enlarged spleen, ascites (fluid accumulation in the abdominal cavity), pruritus (itching), and other signs of liver injury; persons under 40 years of age that develops wheezing, a chronic cough or bronchitis, is short of breath after exertion and/or shows other signs of emphysema (especially when the patient is not a smoker, has not been exposed to known lung irritants, and when the lung damage appears to be located low in the lungs); when you have a close relative with alpha-1 antitrypsin deficiency; when a patient has a decreased level of A1AT.

Elevation of both serum cholesterol and triglycerides; accelerated atherosclerosis, coronary heart disease; cutaneous xanthomas; peripheral vascular disease; diabetes mellitus, obesity or hypothyroidism

Muscle weakness (rapidly progressive); frequent falls; difficulty with motor skills (running, hopping, jumping); progressive difficulty walking (ability to walk may be lost by age 12); fatigue; intellectual retardation (possible); skeletal deformities; chest and back (scoliosis); muscle deformities (contractures of heels, legs; pseudohypertrophy of calf muscles)

Reduced synthesis of the hemoglobin-beta chain; microcytic hypochromic anemia

Venous thrombosis; certain arterial thrombotic conditions; patients with deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, and premature ischemic stroke and also of women with premature myocardial infarction; family history of early onset stroke, deep vein thrombosis, thromboembolism, pregnancy associated with thrombosis/embolism, hyperhomocystinemia, and multiple miscarriage. Individuals with the mutation are at increased risk of thrombosis in the setting of oral contraceptive use, trauma, and surgery.

Venous thrombosis; pulmonary embolism; transient ischemic attack or premature stroke; peripheral vascular disease, particularly lower extremity; occlusive disease; cerebral vein thrombosis; multiple spontaneous abortions; intrauterine fetal demise

Venous thrombosis; increased plasma homocysteine levels

Independent risk factor for coronary artery disease, ischemic stroke, venous thrombosis (including osteonecrosis)

Uncontrolled division of cancer cells

Inflammation confined to the colon; abdominal pain and bloody diarrhea; anal fistulae and peri-rectal abscesses can also occur

Large amount of abnormally thick mucus in the lungs and intestines; leads to congestioni, pneumonia, diarrhea and poor growth

Congenital loss of hearing; -prelingual, non-syndromic deafness

Tendon xanthomas; elevated LDL cholesterol; premature heart disease

Predisposition of acute myeloid leukemia; skeletal abnormalities; radial hypoplasia and vertebral defect and other physical abnormalities, bone marrow failure (pancytopenia), endocrine dysfunction, early onset osteopenia/osteoporosis and lipid abnormalities, spontaneous chromosomal breakage exacerbated by exposure to DNA cross-linking agents.

Mental retardation or learning disabilities of unknown etiology; autism or autistic-like characteristics; women with premature menopause. Subtle dysmorphism, log face with prominent mandible and large ears, macroorchidism in postpubertal males, behavioral abnormalities, due to lack of FMR1 in areas such as the cerebral cortex, amygdala, hippocampus and cerebellum

Characterized by slowly progressive ataxia; typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses

over-absorption of iron; accumulation of iron in vital organs (heart, liver, pancreas); organ damage; heart disease; cancer; liver disease; arthritis; diabetes; infertility; impotence

Absence of ganglia in the gut

Progressive disorder of motor, cognitive, and psychiatric disturbances.

Hypolactasia; persistent diarrhea; abdominal cramps; bloating; nausea; flatus

MEN2A (which affects 60% to 90% of MEN2 families):Medullary thyroid carcinoma; Pheochromocytoma (tumor of the adrenal glands); Parathyroid adenomas (benign [noncancerous] tumors) or hyperplasia (increased size) of the parathyroid gland; MEN2B (which affects 5% of MEN2 families): Medullary thyroid carcinoma; Pheochromocytoma; Mucosal neuromas (benign tumors of nerve tissue on the tongue and lips); Digestive problems; Muscle, joint, and spinal problems; Typical facial features; Familial medullary thyroid carcinoma (FMTC) (which affects 5% to 35% of MEN2 families):Medullary thyroid carcinoma only

Affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system; clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital.

Pseudocholinesterase (also called butyrylcholinesterase or "BCHE") hydrolyzes a number of choline-based compounds including cocaine, heroin, procaine, and succinylcholine, mivacurium, and other fast-acting muscle relaxants.[16] Mutations in the BCHE gene lead to deficiency in the amount or function of the protein, which in turn results in a delay in the metabolism of these compounds, which prolongs their effects. Succinylcholine is commonly used as an anaesthetic in surgical procedures, and a person with BCHE mutations may suffer prolonged paraylasis. Between 1 in 3200 and 1 in 5000 people carry BCHE mutations; they are most prevalent in Persian Jews and Alaska Natives.[16][17] As of 2013 there are 9 genetic tests available.[18]

Variable degrees of hemolysis and intermittent episodes of vascular occlusion resulting in tissue ischemia and acute and chronic organ dysfunction; complications include anemia, jaundice, predisposition to aplastic crisis, sepsis, cholelithiasis, and delayed growth. Diagnosis suspected in infants or young children with painful swelling of the hands and feet, pallor, jaundice, pneumococcal sepsis or meningitis, severe anemia with splenic enlargement, or acute chest syndrome.

Lipids accumulate in the brain; neurological dysfunction; progressive weakness and loss of motor skills; decreased social interaction, seizures, blindness, and total debilitation

Cutaneous photosensitivity; acute neurovisceral crises

Genetic testing is often done as part of a genetic consultation and as of mid-2008 there were more than 1,200 clinically applicable genetic tests available.[19] Once a person decides to proceed with genetic testing, a medical geneticist, genetic counselor, primary care doctor, or specialist can order the test after obtaining informed consent.

Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a medical procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. Alternatively, a small amount of saline mouthwash may be swished in the mouth to collect the cells. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorders, often using DNA sequencing. The laboratory reports the test results in writing to a person's doctor or genetic counselor.

Routine newborn screening tests are done on a small blood sample obtained by pricking the baby's heel with a lancet.

The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but non-negligible risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus.

Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. The potential negative impact of genetic testing has led to an increasing recognition of a "right not to know".[20] In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern. Some individuals avoid genetic testing out of fear it will affect their ability to purchase insurance or find a job.[21] Health insurers do not currently require applicants for coverage to undergo genetic testing, and when insurers encounter genetic information, it is subject to the same confidentiality protections as any other sensitive health information.[22] In the United States, the use of genetic information is governed by the Genetic Information Nondiscrimination Act (GINA) (see discussion below in the section on government regulation).

Genetic testing can provide only limited information about an inherited condition. The test often can't determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed.

A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision.

Direct-to-consumer (DTC) genetic testing is a type of genetic test that is accessible directly to the consumer without having to go through a health care professional. Usually, to obtain a genetic test, health care professionals (such as doctors) acquire their patient's permission and then order the desired test. DTC genetic tests, however, allow consumers to bypass this process and order DNA tests themselves.

There is a variety of DTC tests, ranging from tests for breast cancer alleles to mutations linked to cystic fibrosis. Benefits of DTC testing are the accessibility of tests to consumers, promotion of proactive healthcare, and the privacy of genetic information. Possible additional risks of DTC testing are the lack of governmental regulation, the potential misinterpretation of genetic information, issues related to testing minors, privacy of data, and downstream expenses for the public health care system.[23]

DTC genetic testing has been controversial due to outspoken opposition within the medical community. Critics of DTC testing argue against the risks involved, the unregulated advertising and marketing claims, and the overall lack of governmental oversight.[24]

DTC testing involves many of the same risks associated with any genetic test. One of the more obvious and dangerous of these is the possibility of misreading of test results. Without professional guidance, consumers can potentially misinterpret genetic information, causing them to be deluded about their personal health.

Some advertising for DTC genetic testing has been criticized as conveying an exaggerated and inaccurate message about the connection between genetic information and disease risk, utilizing emotions as a selling factor. An advertisement for a BRCA-predictive genetic test for breast cancer stated: There is no stronger antidote for fear than information.[25]

Ancestry.com, a company providing DTC DNA tests for genealogy purposes, has reportedly allowed the warrantless search of their database by police investigating a murder.[26] The warrantless search led to a search warrant to force the gathering of a DNA sample from a New Orleans filmmaker; however he turned out not to be a match for the suspected killer.[27]

Currently, the U.S. has no strong federal regulation moderating the DTC market. Though there are several hundred tests available, only a handful are approved by the Food and Drug Administration (FDA); these are sold as at-home test kits, and are therefore considered "medical devices" over which the FDA may assert jurisdiction. Other types of DTC tests require customers to mail in DNA samples for testing; it is difficult for the FDA to exercise jurisdiction over these types of tests, because the actual testing is completed in the laboratories of providers. As of 2007, the FDA had not yet officially substantiated with scientific evidence the claimed accuracy of the majority of direct-to-consumer genetic tests.[28]

With regard to genetic testing and information in general, legislation in the United States called the Genetic Information Nondiscrimination Act prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future. The legislation also bars employers from using individuals genetic information when making hiring, firing, job placement, or promotion decisions.[29] The legislation, the first of its kind in the U.S.,[30] was passed by the United States Senate on April 24, 2008, on a vote of 95-0, and was signed into law by President George W. Bush on May 21, 2008.[31][32] It went into effect on November 21, 2009.

In June 2013 the US Supreme Court issued two rulings on human genetics. The Court struck down patents on human genes, opening up competition in the field of genetic testing.[33] The Supreme Court also ruled that police were allowed to collect DNA from people arrested for serious offenses.[34]

The American Academy of Pediatrics (AAP) and the American College of Medical Genetics (ACMG) have provided new guidelines for the ethical issue of pediatrics genetic testing and screening of children in the United States. Their guidelines state that performing pediatric genetic testing should be in the best interest of the child. In hypothetical situations for adults getting genetically tested 84-98% expressing interest in getting genetically tested for cancer predisposition.[35] Though only half who are at risk of would get tested. AAP and ACMG recommend holding off on genetic testing for late-onset conditions until adulthood. Unless diagnosing genetic disorders during childhood and start early intervention can reduce morbidity or mortality. They also state that with parents or guardians permission testing for asymptomatic children who are at risk of childhood onset conditions are ideal reasons for pediatrics genetic testing. Testing for pharmacogenetics and newborn screening is found to be acceptable by AAP and ACMG guidelines. Histocompatibility testing guideline states that its permissible for children of all ages to have tissue compatibility testing for immediate family members but only after the psychosocial, emotional and physical implications has been explored. With a donor advocate or similar mechanism should be in place to protect the minors from coercion and to safeguard the interest of said minor. Both AAP and ACMG discourage the use of direct-to-consumer and home kit genetic because of the accuracy, interpretation and oversight of test content. Guidelines also state that if parents or guardians should be encouraged to inform their child of the results from the genetic test if the minor is of appropriate age. If minor is of mature appropriate age and request results, the request should be honored. Though for ethical and legal reasons health care providers should be cautions in providing minors with predictive genetic testing without the involvement of parents or guardians. Within the guidelines AAP and ACMG state that health care provider have an obligation to inform parents or guardians on the implication of test results. To encourage patients and families to share information and even offer help in explain results to extend family or refer them to genetic counseling. AAP and ACMG state any type of predictive genetic testing for all types is best offer with genetic counseling being offer by Clinical genetics, genetic counselors or health care providers.[35][36][37]

Israel uses DNA testing to determine if people are eligible for legal privileges given to specific ethnic groups. The policy where "many Jews from the Former Soviet Union (FSU) are asked to provide DNA confirmation of their Jewish heritage in order to immigrate as Jews and become citizens under Israel's Law of Return" has generated controversy. [38]

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Genetic testing - Wikipedia

Frequently Asked Questions About Genetic Testing What is genetic testing?

Genetic testing uses laboratory methods to look at your genes, which are the DNA instructions you inherit from your mother and your father. Genetic tests may be used to identify increased risks of health problems, to choose treatments, or to assess responses to treatments.

There are many different types of genetic tests. Genetic tests can help to:

Genetic test results can be hard to understand, however specialists like geneticists and genetic counselors can help explain what results might mean to you and your family. Because genetic testing tells you information about your DNA, which is shared with other family members, sometimes a genetic test result may have implications for blood relatives of the person who had testing.

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Diagnostic testing is used to precisely identify the disease that is making a person ill. The results of a diagnostic test may help you make choices about how to treat or manage your health.

Predictive and pre-symptomatic genetic tests are used to find gene changes that increase a person's likelihood of developing diseases. The results of these tests provide you with information about your risk of developing a specific disease. Such information may be useful in decisions about your lifestyle and healthcare.

Carrier testing is used to find people who "carry" a change in a gene that is linked to disease. Carriers may show no signs of the disease; however, they have the ability to pass on the gene change to their children, who may develop the disease or become carriers themselves. Some diseases require a gene change to be inherited from both parents for the disease to occur. This type of testing usually is offered to people who have a family history of a specific inherited disease or who belong to certain ethnic groups that have a higher risk of specific inherited diseases.

Prenatal testing is offered during pregnancy to help identify fetuses that have certain diseases.

Newborn screening is used to test babies one or two days after birth to find out if they have certain diseases known to cause problems with health and development.

Pharmacogenomic testing gives information about how certain medicines are processed by an individual's body. This type of testing can help your healthcare provider choose the medicines that work best with your genetic makeup.

Research genetic testing is used to learn more about the contributions of genes to health and to disease. Sometimes the results may not be directly helpful to participants, but they may benefit others by helping researchers expand their understanding of the human body, health, and disease.

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Benefits: Genetic testing may be beneficial whether the test identifies a mutation or not. For some people, test results serve as a relief, eliminating some of the uncertainty surrounding their health. These results may also help doctors make recommendations for treatment or monitoring, and give people more information for making decisions about their and their family's health, allowing them to take steps to lower his/her chance of developing a disease. For example, as the result of such a finding, someone could be screened earlier and more frequently for the disease and/or could make changes to health habits like diet and exercise. Such a genetic test result can lower a person's feelings of uncertainty, and this information can also help people to make informed choices about their future, such as whether to have a baby.

Drawbacks: Genetic testing has a generally low risk of negatively impacting your physical health. However, it can be difficult financially or emotionally to find out your results.

Emotional: Learning that you or someone in your family has or is at risk for a disease can be scary. Some people can also feel guilty, angry, anxious, or depressed when they find out their results.

Financial: Genetic testing can cost anywhere from less than $100 to more than $2,000. Health insurance companies may cover part or all of the cost of testing.

Many people are worried about discrimination based on their genetic test results. In 2008, Congress enacted the Genetic Information Nondiscrimination Act (GINA) to protect people from discrimination by their health insurance provider or employer. GINA does not apply to long-term care, disability, or life insurance providers. (For more information about genetic discrimination and GINA, see http://www.genome.gov/10002328/Genetic-Discrimination-Fact-Sheet).

Limitations of testing: Genetic testing cannot tell you everything about inherited diseases. For example, a positive result does not always mean you will develop a disease, and it is hard to predict how severe symptoms may be. Geneticists and genetic counselors can talk more specifically about what a particular test will or will not tell you, and can help you decide whether to undergo testing.

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There are many reasons that people might get genetic testing. Doctors might suggest a genetic test if patients or their families have certain patterns of disease. Genetic testing is voluntary and the decision about whether to have genetic testing is complex.

A geneticist or genetic counselor can help families think about the benefits and limitations of a particular genetic test. Genetic counselors help individuals and families understand the scientific, emotional, and ethical factors surrounding the decision to have genetic testing and how to deal with the results of those tests. (See: Frequently Asked Questions about Genetic Counseling)

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Talking Glossary of Genetic Terms

Genetic Testing From Genetics Home Reference: the benefits, costs, risks and limitations of genetic testing.

Genetic Testing Registry [ncbi.nlm.nih.gov] A publicly funded medical genetics information resource developed for physicians, other healthcare providers, and researchers.

Prenatal Screening [marchofdimes.com] Provides prenatal testing information, including ultrasound, amniocentesis and chorionic villus sampling (CVS).

National Newborn Screening & Genetics Resource Center [genes-r-us.uthscsa.edu] Provides information and resources in the area of newborn screening and genetics.

Genetic Alliance- Genes in Life [genesinlife.org] A guide from the Genetic Alliance with easy-to-read information about genetic testing.

Genetics and Cancer [cancer.gov] An information fact sheet from the National Cancer Institute about genetic testing for hereditary cancers.

Find a Genetic Counselor [nsgc.org] A search engine developed by the National Society of Genetic Counselors.

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Last Updated: August 27, 2015

See original here:
FAQ About Genetic Testing - National Human Genome Research ...

What are BRCA1 and BRCA2?

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cells genetic material. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers (1) and about 5 to 10 percent of all breast cancers (2). In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall (3). Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts.

A harmful BRCA1 or BRCA2 mutation can be inherited from a persons mother or father. Each child of a parent who carries a mutation in one of these genes has a 50 percent chance (or 1 chance in 2) of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a persons second copy of the gene is normal.

How much does having a BRCA1 or BRCA2 gene mutation increase a womans risk of breast and ovarian cancer?

A womans lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.

Breast cancer: About 12 percent of women in the general population will develop breast cancer sometime during their lives (4). By contrast, according to the most recent estimates, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years (5, 6).

Ovarian cancer: About 1.3 percent of women in the general population will develop ovarian cancer sometime during their lives (4). By contrast, according to the most recent estimates, 39 percent of women who inherit a harmful BRCA1 mutation (5, 6) and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years (5, 6).

It is important to note that these estimated percentages of lifetime risk are different from those available previously; the estimates have changed as more information has become available, and they may change again with additional research. No long-term general population studies have directly compared cancer risk in women who have and do not have a harmful BRCA1 or BRCA2 mutation.

It is also important to note that other characteristics of a particular woman can make her cancer risk higher or lower than the average risks. These characteristics include her family history ofbreast, ovarian, and, possibly, other cancers; the specific mutation(s) she has inherited; and other risk factors, suchas her reproductivehistory. However, at this time, based on current data, none of these other factors seems to be as strong as the effect of carrying a harmful BRCA1 or BRCA2 mutation.

What other cancers have been linked to mutations in BRCA1 and BRCA2?

Are mutations in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?

Yes. For example, people of Ashkenazi Jewish descent have a higher prevalence of harmful BRCA1 and BRCA2 mutations than people in the general U.S. population. Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have a higher prevalence of specific harmful BRCA1 and BRCA2 mutations.

In addition, limited data indicate that the prevalence of specific harmful BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (15, 16).

Are genetic tests available to detect BRCA1 and BRCA2 mutations?

Yes. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member) and tests that check for all possible mutations in both genes. DNA (from a blood or saliva sample) is needed for mutation testing. The sample is sent to a laboratory for analysis. It usually takes about a month to get the test results.

Who should consider genetic testing for BRCA1 and BRCA2 mutations?

Because harmful BRCA1 and BRCA2 gene mutations are relatively rare in the general population, most experts agree that mutation testing of individuals who do not have cancer should be performed only when the persons individual or family history suggests the possible presence of a harmful mutation in BRCA1 or BRCA2.

In December 2013, the United States Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a family history that is associated with an increased risk of a harmful mutation in one of these genes (17).

Several screening tools are now available to help health care providers with this evaluation (17). These tools assess family history factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, including:

When an individual has a family history that is suggestive of the presence of a BRCA1 or BRCA2 mutation, it may be most informative to first test a family member who has cancer if that person is still alive and willing to be tested. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members may want to consider genetic counseling to learn more about their potential risks and whether genetic testing for mutations in BRCA1 and BRCA2 might be appropriate for them.

If it is not possible to confirm the presence of a harmful BRCA1 or BRCA2 mutation in a family member who has cancer, it is appropriate for both men and women who do not have cancer but have a family medical history that suggests the presence of such a mutation to have genetic counseling for possible testing.

Some individualsfor example, those who were adopted at birthmay not know their family history. In cases where a woman with an unknown family history has an early-onset breast cancer or ovarian cancer or a man with an unknown family history is diagnosed with breast cancer, it may be reasonable for that individual to consider genetic testing for a BRCA1 or BRCA2 mutation. Individuals with an unknown family history who do not have an early-onset cancer or male breast cancer are at very low risk of having a harmful BRCA1 or BRCA2 mutation and are unlikely to benefit from routine genetic testing.

Professional societies do not recommend that children, even those with a family history suggestive of a harmful BRCA1 or BRCA2 mutation, undergo genetic testing for BRCA1 or BRCA2. This is because no risk-reduction strategies exist for children, and children's risks of developing a cancer type associated with a BRCA1 or BRCA2 mutation are extremely low. After children with a family history suggestive of a harmful BRCA1 or BRCA2 mutation become adults, however, they may want to obtain genetic counseling about whether or not to undergoing genetic testing.

Should people considering genetic testing for BRCA1 and BRCA2 mutations talk with a genetic counselor?

Genetic counseling is generally recommended before and after any genetic test for an inherited cancer syndrome. This counseling should be performed by a health care professional who is experienced in cancer genetics. Genetic counseling usually covers many aspects of the testing process, including:

How much does BRCA1 and BRCA2 mutation testing cost?

The Affordable Care Act considers genetic counseling and BRCA1 and BRCA2 mutation testing for individuals at high risk a covered preventive service. People considering BRCA1 and BRCA2 mutation testing may want to confirm their insurance coverage for genetic tests before having the test.

Some of the genetic testing companies that offer testing for BRCA1 and BRCA2 mutations may offer testing at no charge to patients who lack insurance and meet specific financial and medical criteria.

What does a positive BRCA1 or BRCA2 genetic test result mean?

BRCA1 and BRCA2 gene mutation testing can give several possible results: a positive result, a negative result, or an ambiguous or uncertain result.

A positive test result indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when an individual will actually develop cancer. For example, some women who inherit a harmful BRCA1 or BRCA2 mutation will never develop breast or ovarian cancer.

A positive genetic test result may also have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that persons relatives:

What does a negative BRCA1 or BRCA2 test result mean?

A negative test result can be more difficult to understand than a positive result because what the result means depends in part on an individuals family history of cancer and whether a BRCA1 or BRCA2 mutation has been identified in a blood relative.

If a close (first- or second-degree) relative of the tested person is known to carry a harmful BRCA1 or BRCA2 mutation, a negative test result is clear: it means that person does not carry the harmful mutation that is responsible for the familial cancer, and thus cannot pass it on to their children. Such a test result is called a true negative. A person with such a test result is currently thought to have the same risk of cancer as someone in the general population.

If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but complete gene testing identifies no such mutation in the family, a negative result is less clear. The likelihood that genetic testing will miss a known harmful BRCA1 or BRCA2 mutation is very low, but it could happen. Moreover, scientists continue to discover new BRCA1 and BRCA2 mutations and have not yet identified all potentially harmful ones. Therefore, it is possible that a person in this scenario with a "negative" test result actually has an as-yet unknown harmful BRCA1 or BRCA2 mutation that has not been identified.

It is also possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test used. People considering genetic testing for BRCA1 and BRCA2 mutations may want to discuss these potential uncertainties with a genetic counselor before undergoing testing.

What does an ambiguous or uncertain BRCA1 or BRCA2 test result mean?

Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer. This type of test result may be described as ambiguous (often referred to as a genetic variant of uncertain significance) because it isnt known whether this specific gene change affects a persons risk of developing cancer. One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (18).

As more research is conducted and more people are tested for BRCA1 and BRCA2 mutations, scientists will learn more about these changes and cancer risk. Genetic counseling can help a person understand what an ambiguous change in BRCA1 or BRCA2 may mean in terms of cancer risk. Over time, additional studies of variants of uncertain significance may result in a specific mutation being re-classified as either harmful or clearly not harmful.

How can a person who has a positive test result manage their risk of cancer?

Several options are available for managing cancer risk in individuals who have a known harmful BRCA1 or BRCA2 mutation. These include enhanced screening, prophylactic (risk-reducing) surgery, and chemoprevention.

Enhanced Screening. Some women who test positive for BRCA1 and BRCA2 mutations may choose to start cancer screening at younger ages than the general population or to have more frequent screening. For example, some experts recommend that women who carry a harmful BRCA1 or BRCA2 mutation undergo clinical breast examinations beginning at age 25 to 35 years (19). And some expert groups recommend that women who carry such a mutation have a mammogram every year, beginning at age 25 to 35 years.

Enhanced screening may increase the chance of detecting breast cancer at an early stage, when it may have a better chance of being treated successfully. Women who have a positive test result should ask their health care provider about the possible harms of diagnostic tests that involve radiation (mammograms or x-rays).

Recent studies have shown that MRI may be more sensitive than mammography for women at high risk of breast cancer (20, 21). However, mammography can also identify some breast cancers that are not identified by MRI (22), and MRI may be less specific (i.e., lead to more false-positive results) than mammography. Several organizations, such as the American Cancer Society and the National Comprehensive Cancer Network, now recommend annual screening with mammography and MRI for women who have a high risk of breast cancer.

No effective ovarian cancer screening methods currently exist. Some groups recommend transvaginal ultrasound, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer (23). For a screening method to be considered effective, it must have demonstrated reduced mortality from the disease of interest. This standard has not yet been met for ovarian cancer screening.

The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 is also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular mammography as well as testing for prostate cancer. The value of these screening strategies remains unproven at present.

Prophylactic (Risk-reducing) Surgery. Prophylactic surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (bilateral prophylactic mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes (bilateral prophylactic salpingo-oophorectomy) can help reduce her risk of ovarian cancer. Removing the ovaries also reduces the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer.

No evidence is available regarding the effectiveness of bilateral prophylactic mastectomy in reducing breast cancer risk in men with a harmful BRCA1 or BRCA2 mutation or a family history of breast cancer. Therefore, bilateral prophylactic mastectomy for men at high risk of breast cancer is considered an experimental procedure, and insurance companies will not normally cover it.

Prophylactic surgery does not completely guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. Nevertheless, the mortality reduction associated with this surgery is substantial: Research demonstrates that women who underwent bilateral prophylactic salpingo-oophorectomy had a nearly 80 percent reduction in risk of dying from ovarian cancer, a 56 percent reduction in risk of dying from breast cancer (24), and a 77 percent reduction in risk of dying from any cause (25).

Emerging evidence (25) suggests that the amount of protection that removing the ovaries and fallopian tubes provides against the development of breast and ovarian cancer may be similar for carriers of BRCA1 and BRCA2 mutations, in contrast to earlier studies (26).

Chemoprevention. Chemoprevention is the use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the recurrence of, cancer. Although two chemopreventive drugs (tamoxifen and raloxifene) have been approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk, the role of these drugs in women with harmful BRCA1 or BRCA2 mutations is not yet clear.

Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (27), including the risk of cancer in the opposite breast among women previously diagnosed with breast cancer (28, 29). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 mutation carriers specifically.

Oral contraceptives (birth control pills) are thought to reduce the risk of ovarian cancer by about 50 percent both in the general population and in women with harmful BRCA1 or BRCA2 mutations (30).

What are some of the benefits of genetic testing for breast and ovarian cancer risk?

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one's children are not at risk of inheriting the family's cancer susceptibility, and the possibility that special checkups, tests, or preventive surgeries may not be needed.

A positive test result may bring relief by resolving uncertainty regarding future cancer risk and may allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, people who have a positive test result may choose to participate in medical research that could, in the long run, help reduce deaths from hereditary breast and ovarian cancer.

What are some of the possible harms of genetic testing for breast and ovarian cancer risk?

The direct medical harms of genetic testing are minimal, but knowledge of test results may have harmful effects on a persons emotions, social relationships, finances, and medical choices.

People who receive a positive test result may feel anxious, depressed, or angry. They may have difficulty making choices about whether to have preventive surgery or about which surgery to have.

People who receive a negative test result may experience survivor guilt, caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.

Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal life choices, such as decisions about career, marriage, and childbearing.

Violations of privacy and of the confidentiality of genetic test results are additional potential risks. However, the federal Health Insurance Portability and Accountability Act and various state laws protect the privacy of a persons genetic information. Moreover, the federal Genetic Information Nondiscrimination Act, along with many state laws, prohibits discrimination based on genetic information in relation to health insurance and employment, although it does not cover life insurance, disability insurance, or long-term care insurance.

Finally, there is a small chance that test results may not be accurate, leading people to make decisions based on incorrect information. Although inaccurate results are unlikely, people with these concerns should address them during genetic counseling.

What are the implications of having a harmful BRCA1 or BRCA2 mutation for breast and ovarian cancer prognosis and treatment?

A number of studies have investigated possible clinical differences between breast and ovarian cancers that are associated with harmful BRCA1 or BRCA2 mutations and cancers that are not associated with these mutations.

There is some evidence that, over the long term, women who carry these mutations are more likely to develop a second cancer in either the same (ipsilateral) breast or the opposite (contralateral) breast than women who do not carry these mutations. Thus, some women with a harmful BRCA1 or BRCA2 mutation who develop breast cancer in one breast opt for a bilateral mastectomy, even if they would otherwise be candidates for breast-conserving surgery. In fact, because of the increased risk of a second breast cancer among BRCA1 and BRCA2 mutation carriers, some doctors recommend that women with early-onset breast cancer and those whose family history is consistent with a mutation in one of these genes have genetic testing when breast cancer is diagnosed.

Breast cancers in women with a harmful BRCA1 mutation are also more likely to be "triple-negative cancers" (i.e., the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein), which generally have poorer prognosis than other breast cancers.

Because the products of the BRCA1 and BRCA2 genes are involved in DNA repair, some investigators have suggested that cancer cells with a harmful mutation in either of these genes may be more sensitive to anticancer agents that act by damaging DNA, such as cisplatin. In preclinical studies, drugs called PARP inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have BRCA1 or BRCA2 mutations. These drugs have also shown some activity in cancer patients who carry BRCA1 or BRCA2 mutations, and researchers are continuing to develop and test these drugs.

What research is currently being done to help individuals with harmful BRCA1 or BRCA2 mutations?

Research studies are being conducted to find new and better ways of detecting, treating, and preventing cancer in people who carry mutations in BRCA1 and BRCA2. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.

Information about active clinical trials (research studies with people) for individuals with BRCA1 or BRCA2 mutations is available on NCIs website. The following links will retrieve lists of clinical trials open to individuals with BRCA1 or BRCA2 mutations.

NCIs Cancer Information Service (CIS) can also provide information about clinical trials and help with clinical trial searches.

Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?

Yes. Although harmful mutations in BRCA1 and BRCA2 are responsible for the disease in nearly half of families with multiple cases of breast cancer and up to 90 percent of families with both breast and ovarian cancer, mutations in a number of other genes have been associated with increased risks of breast and/or ovarian cancers (2, 31). These other genes include several that are associated with the inherited disorders Cowden syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, and Fanconi anemia, which increase the risk of many cancer types.

Most mutations in these other genes are associated with smaller increases in breast cancer risk than are seen with mutations in BRCA1 and BRCA2. However, researchers recently reported that inherited mutations in the PALB2 gene are associated with a risk of breast cancer nearly as high as that associated with inherited BRCA1 and BRCA2 mutations (32). They estimated that 33 percent of women who inherit a harmful mutation in PALB2 will develop breast cancer by age 70 years. The estimated risk of breast cancer associated with a harmful PALB2 mutation is even higher for women who have a family history of breast cancer: 58 percent of those women will develop breast cancer by age 70 years.

PALB2, like BRCA1 and BRCA2, is a tumor suppressor gene. The PALB2 gene produces a protein that interacts with the proteins produced by the BRCA1 and BRCA2 genes to help repair breaks in DNA. Harmful mutations in PALB2 (also known as FANCN) are associated with increased risks of ovarian, pancreatic, and prostate cancers in addition to an increased risk of breast cancer (13, 33, 34). Mutations in PALB2, when inherited from each parent, can cause a Fanconi anemia subtype, FA-N, that is associated with childhood solid tumors (13, 33, 35).

Although genetic testing for PALB2 mutations is available, expert groups have not yet developed specific guidelines for who should be tested for, or the management of breast cancer risk in individuals with, PALB2 mutations.

Originally posted here:
BRCA1 and BRCA2: Cancer Risk and Genetic Testing Fact Sheet ...

The FSH Society receives numerous inquiries about understanding genetic test results.

The following excerpts are from Deymeer F (ed): Neuromuscular Diseases: From Basic Mechanisms to Clinical Management. Clin Neurosci. Basel, Karger, 2000. vol 18. pp 44-60. The chapter title Facioscapulohumeral Muscular Dystrophy: Diagnostic and Molecular Aspects is by Peter Lunt, Ph.D., Clinical Genetics Unit, Bristol Royal Hospital for Sick Children, Bristol, UK.

Pages 48-49 have a section headed Molecular Testing: Confirmation of Diagnosis that states: In 90-95% of cases of FSHD, as defined by meeting the diagnostic criteria, the diagnosis can effectively be confirmed by showing the presence of a shortened (<35 kb) DNA fragment at 4q35 (recognized by probe pl3E-11), which arises from deletion of an integral number of copies of the 3.3-kb repeats from that region. The DNA probe used (pl3E-11) also detects the closely homologous 3.3-kb repeat array from 10q26. However, each chromosome 10-type repeat has an additional BlnI restriction site. For the specific diagnostic test, a double digest with EcoRi/BlnI is employed on genomic DNA (obtained from peripheral blood), which removes chromosome 10-type repeats, but leaves chromosome 4-type repeats intact (albeit reduced by 3 kb in size compared to EcoR1 single digest) {Source: Neuromuscular Diseases: From Basic Mechanisms to Clinical Management.Chapter p 48-49 Facioscapulohumeral Muscular Dystrophy: Diagnostic and Molecular Aspects, by Peter Lunt, Ph.D.]

Page 45 of the chapter defines the generally accepted correlation between clinical severity and D4Z4 repeat number calculation. It is found that the age at onset and severity of clinical presentation correlates broadly and inversely with the size of the residual DNA fragment at 4q35, and, by inference, therefore correlates directly with the number of repeat units deleted. Thus, the smallest residual fragment lengths at 10-17 kb (1-3 repeat copies) are usually associated with a severe infantile or childhood presentation, medium lengths (18 30 kb, or 4-7 repeat copies) are often found in the largest recognised dominant families, while the largest lengths (31-38 kb, or 8-10 repeat copies) have been associated with a milder predominantly scapulohumeral presentation and may well have reduced penetrance, particularly in females. New mutation cases are seen predominantly with the smallest residual fragment lengths, giving matching clinical severity, and may originate predominantly on the maternal copy of chromosome 4. Study of parental DNA suggests that around 20-30% of new mutations occur as somatic and germline events in one of the parents, this usually also being the mother.

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Genetic testing - FSH Society

Research has shown that up to 10 percent of cancers are due to factors that are passed from one generation to the next. These syndromes are known as hereditary cancers and there are genetic tests that can be used to determine an individuals risk for developing these cancers. If you suspect that you or someone you know may be at risk for cancer - such as a family history of cancer or membership in an at-risk ethnic population (such as people with Ashkenazi Jewish ancestry) - you may want to talk to your healthcare professional about genetic testing.

There are many benefits to getting tested, regardless of the eventual result. If one of your family members however distant had cancer, there is a chance that you inherited a gene mutation that not only increases your personal risk of cancer, but also could be passed to the next generation. Those who are carriers of hereditary cancer gene mutations, could be at risk of getting cancer earlier in life than the general population. The sooner genetic testing is done, the more likely it is that the risk can be managed appropriately.

Remember: Your healthcare professional is your most valuable source of information and advice about hereditary cancer screening.

Myriads Hereditary Cancer Quiz helps you to assess whether you might be a candidate for hereditary cancer genetic testing.

Click here to take the easy, 30-second Hereditary Cancer Quiz.

Read more from the original source:
Myriad Genetics | Patients & Families | Genetic Testing 101

Some types of cancer run in certain families, but most cancers are not clearly linked to the genes we inherit from our parents. Gene changes that start in a single cell over the course of a person's life cause most cancers. In this section you can learn more about the complex links between genes and cancer.

Cancer is such a common disease that it is no surprise that many families have at least a few members who have had cancer. Sometimes, certain types of cancer seem to run in some families. But only a small portion of all cancers are inherited. This document focuses on those cancers.

Advances in genetics and molecular biology have improved our knowledge of the inner workings of cells, the basic building blocks of the body. Here we review how cells can change during a persons life to become cancer, how certain types of changes can build on inherited gene changes to speed up the development of cancer, and how this information can help us better prevent and treat cancer.

Genetic testing can be useful for people with certain types of cancer that seem to run in their families, but these tests aren't recommended for everyone. Here we offer basic information to help you understand what genetic testing is and how it is used in cancer.

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Genetics and Cancer | American Cancer Society

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Prepared by

Bin Chen, PhD

MariBeth Gagnon, MS

Shahram Shahangian, PhD

Nancy L. Anderson, MMSc

Devery A. Howerton, PhD

D. Joe Boone, PhD

Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, Coordinating Center for Infectious Diseases

The material in this report originated in the Coordinating Center for Infectious Diseases, Mitchell L. Cohen, MD, Director; National Center for Preparedness, Detection, and Control of Infectious Diseases, Rima Khabbaz, MD, Director; and the Division of Laboratory Systems, Roberta B. Carey, PhD, Acting Director.

Corresponding preparer: Bin Chen, PhD, Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, Coordinating Center for Infectious Diseases, 1600 Clifton Road NE, MS G-23, Atlanta, GA 30329. Telephone: 404-498-2228; Fax: 404-498-2215; E-mail: bkc1@cdc.gov.

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized as waived (from routine regulatory oversight) or nonwaived based on the complexity of the tests; tests of moderate and high complexity are nonwaived tests. Laboratories that perform molecular genetic testing are subject to the general CLIA quality systems requirements for nonwaived testing and the CLIA personnel requirements for tests of high complexity. Although many laboratories that perform molecular genetic testing comply with applicable regulatory requirements and adhere to professional practice guidelines,specific guidelines for quality assurance are needed to ensure the quality of test performance. To enhance the oversight of genetic testing under the CLIA framework,CDC and the Centers for Medicare & Medicaid Services (CMS) have taken practical steps to address the quality management concerns in molecular genetic testing,including working with the Clinical Laboratory Improvement Advisory Committee (CLIAC). This report provides CLIAC recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. The recommended practices address the total testing process (including the preanalytic,analytic,and postanalytic phases),laboratory responsibilities regarding authorized persons,confidentiality of patient information,personnel competency,considerations before introducing molecular genetic testing or offering new molecular genetic tests,and the quality management system approach to molecular genetic testing. These recommendations are intended for laboratories that perform molecular genetic testing for heritable diseases and conditions and for medical and public health professionals who evaluate laboratory practices and policies to improve the quality of molecular genetic laboratory services. This report also is intended to be a resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care. Improvements in the quality and use of genetic laboratory services should improve the quality of health care and health outcomes for patients and families of patients.

Genetic testing encompasses a broad range of laboratory tests performed to analyze DNA, RNA, chromosomes, proteins, and certain metabolites using biochemical, cytogenetic, or molecular methods or a combination of these methods. In 1992, the regulations for the Clinical Laboratory Improvement Amendments of 1988 (CLIA) were published and began to be implemented. Since that time, advances in scientific research and technology have led to a substantial increase both in the health conditions for which genetic defects or variations can be detected with molecular methods and in the spectrum of the molecular testing methods (1). As the number of molecular genetic tests performed for patient testing has steadily increased, so has the number of laboratories that perform molecular genetic testing for heritable diseases and conditions (2,3). With increasing use in clinical and public health practices, molecular genetic testing affects persons and their families in every life stage by contributing to disease diagnosis, prediction of future disease risk, optimization of treatment, prevention of adverse drug response, and health assessment and management. For example, preconception testing for cystic fibrosis and other heritable diseases has become standard practice for the care of women who are either pregnant or considering pregnancy and are at risk for giving birth to an infant with one of these conditions (4). DNA-based diagnostic testing often is crucial for confirming presumptive results from newborn screening tests, which are performed forapproximately95% of the 4 million infants born in the United States each year (5,6). In addition, pharmacogenetic and pharmacogenomic tests, which identify individual variations in single-nucleotide polymorphisms, haplotype markers, or alterations in gene expression, are considered essential for personalized medicine, which involves customizing medical care on the basis of genetic information (7).

The expanding field of molecular genetic testing has prompted measures both in the United States and worldwide to assess factors that affect the quality of performance and delivery of testing services, the adequacy of oversight and quality assurance mechanisms, and the areas of laboratory practice in need of improvement. Problems that could affect patient testing outcomes that have been reported include inadequate establishment or verification of test performance specifications, inadequate personnel training or qualifications, inappropriate test selection and specimen submission, inadequate quality assurance practices, problems in proficiency testing, misunderstanding or misinterpretation of test results, and other concerns associated with one or more phases of the testing process (8--11).

Under CLIA, laboratory testing is categorized as waived testing or nonwaived (which includes tests of moderate and high complexity) based on the level of testing complexity. Laboratories that perform molecular genetic testing are subject to general CLIA requirements for nonwaived testing and CLIA personnel requirements for high-complexity testing; no molecular genetic test has been categorized as waived or moderate complexity. Many laboratories also adhere to professional practice guidelines and voluntary or accreditation standards, such as those developed by the American College of Medical Genetics (ACMG), the Clinical and Laboratory Standards Institute (CLSI), and the College of American Pathologists (CAP), which provide specific guidance for molecular genetic testing (12--14). In addition, certain state programs, such as the New York State Clinical Laboratory Evaluation Program (CLEP), have specific requirements that apply to genetic testing laboratories in their purview (15). However, no specific requirements exist at the federal level for laboratory performance of molecular genetic testing for heritable diseases and conditions.

Since 1997, CDC and the Centers for Medicare & Medicaid Services (CMS) have worked with other federal agencies, professional organizations, standard-setting organizations, CLIAC, and other advisory committees to promote the quality of genetic testing and improve the appropriate use of genetic tests in health care. To enhance the oversight of genetic testing under CLIA, CMS developed a multifaceted action plan aimed at providing guidelines, including the good laboratory practice recommendations in this report, rather than prescriptive regulations (16). Many of the activities in the action plan have been implemented or are in progress, including 1) providing CMS and state CLIA surveyors with guidelines and technical training on assessing genetic testing laboratories for compliance with applicable CLIA requirements, 2) developing educational materials on CLIA compliance for genetic testing laboratories, 3) collecting data on laboratory performance in genetic testing, 4) working with CLIAC and standard-setting organizations on oversight concerns, and 5) collaborating with CDC and the Food and Drug Administration (FDA) on ongoing oversight activities (16). This plan also was supported by the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) in its 2008 report providing recommendations regarding future oversight of genetic testing (1).

The purposes of this report are to 1) highlight areas of molecular genetic testing that have been recognized by CLIAC as needing specific guidelines for compliance with existing CLIA requirements or needing quality assurance measures in addition to CLIA requirements and 2) provide CLIAC recommendations for good laboratory practices to ensure the quality of molecular genetic testing for heritable diseases and conditions. These recommendations are intended primarily for genetic testing that is conducted to diagnose, prevent, or treat disease or for health assessment purposes. The recommendations are distinct from the good laboratory practice regulations for nonclinical laboratory studies under FDA oversight (21 CFR Part 58) (17).The recommended laboratory practices provide guidelines for ensuring the quality of the testing process (including the preanalytic, analytic, and postanalytic phases of molecular genetic testing), laboratory responsibilities regarding authorized persons, confidentiality of patient information, and personnel competency. The recommendations also address factors to consider before introducing molecular genetic testing or offering new molecular genetic tests and the quality management system approach in molecular genetic testing. Implementation of the recommendations in laboratories that perform molecular genetic testing for heritable diseases and conditions and an understanding of these recommendations by users of laboratory services are expected to prevent or reduce errors and problems related to test selection and requests, specimen submission, test performance, and reporting and interpretation of results, leading to improved use of molecular genetic laboratory services, better health outcome for patients, and in many instances, better health outcomes for families of patients. In future reports, recommendations will be provided for good laboratory practices focusing on other areas of genetic testing, such as biochemical genetic testing, molecular cytogenetic testing, and somatic genetic testing.

With the completion of the human genome project, discoveries linking genetic mutations or variations to specific diseases and biologic processes are frequently reported (18). The rapid progress in biomedical research, accompanied by advances in laboratory technology, have led to increased opportunities for development and implementation of new molecular genetic tests. For example, the number of heritable diseases and conditions for which clinical genetic tests are available more than tripled in 8 years, from 423 diseases in November 2000 to approximately 1,300 diseases and conditions in October 2008 (2,19). Molecular genetic testing is performed not only to detect or confirm rare genetic diseases or heritable conditions (20) but also to detect mutations or genetic variations associated with more common and complex conditions such as cancer (21,22), coagulation disorders (23), cardiovascular diseases (24), and diabetes (25). As the rapid pace of genetic research results in a better understanding of the role of genetic variations in diseases and health conditions, the development and clinical use of molecular genetic tests continues to expand (26--28).

Despite considerable information gaps regarding the number of U.S. laboratories that perform molecular genetic tests for heritable diseases and conditions and the number of specific genetic tests being performed (1), molecular genetic testing is one of the areas of laboratory testing that is increasing most rapidly. Molecular genetic tests are performed by a broad range of laboratories, including laboratories that have CLIA certificates for chemistry, pathology, clinical cytogenetics, or other specialties or subspecialties (11). Although nationwide data are not available, data from state programs indicate considerable increases in the numbers of laboratories that perform molecular genetic tests. For example, the number of approved laboratories in the state of New York that perform molecular genetic testing for heritable diseases and conditions increased 36% in 6 years, from 25 laboratories in February 2002 to 34 laboratories in October 2008 (29).

Although comprehensive data on the annual number of molecular genetic tests performed nationwide are not available, industry reports indicate a steady increase in the number of common molecular genetic tests for heritable diseases and conditions, such as mutation testing for cystic fibrosis and factor V Leiden thrombophilia (3). The number of cystic fibrosis mutation tests has increased significantly since 2001, pursuant to the recommendations of the American College of Obstetricians and Gynecologists and ACMG for preconception and prenatal carrier screening (30,31). The DNA-based cystic fibrosis mutation tests are now considered to be some of the most commonly performed genetic tests in the United States and have become an essential component of several state newborn screening programs for confirming presumptive screening results of infants (32). The overall increase in molecular genetic testing from 2006 to 2007 worldwide has been reported to be 15% in some market analyses, outpacing other areas of molecular diagnostic testing (33).

In 1988, Congress enacted Public Law 100-578, a revision of Section 353 of the Public Health Service Act (42 U.S.C. 263a) that amended the Clinical Laboratory Improvement Act of 1967 and required the Department of Health and Human Services (HHS) to establish regulations to ensure the quality and reliability of laboratory testing on human specimens for disease diagnosis, prevention, or treatment or for health assessment purposes. In 1992, HHS published CLIA regulations that describe requirements for all laboratories that perform patient testing (34). Facilities that perform testing for forensic purposes only and research laboratories that test human specimens but do not report patient-specific results are exempt from CLIA regulations (34). CMS (formerly the Health Care Financing Administration) administers the CLIA laboratory certification program in conjunction with FDA and CDC. FDA is responsible for test categorization, and CDC is responsible for CLIA studies, convening CLIAC, and providing scientific and technical support to CMS. CLIAC was chartered by HHS to provide recommendations and advice regarding CLIA regulations, the impact of CLIA regulations on medical and laboratory practices, and modifications needed to CLIA standards to accommodate technological advances.

In 2003, CMS and CDC published CLIA regulatory revisions to reorganize and revise CLIA requirements for quality systems for nonwaived testing and the laboratory director qualifications for high-complexity testing (35). The revised regulations included facility administration and quality system requirements for every phase of the testing process (35). Requirements for the clinical cytogenetics specialty also were reorganized and revised. Other genetic tests, such as molecular genetic tests, are not recognized as a specialty or subspecialty under CLIA. However, because these tests are considered high complexity, laboratories that perform molecular genetic testing for heritable diseases and conditions must meet applicable general CLIA requirements for nonwaived testing and the personnel requirements for high-complexity testing (36).

To enhance oversight of genetic testing under CLIA, CMS developed a plan to promote a comprehensive approach for effective application of current regulations and to provide training and guidelines to surveyors and laboratories that perform genetic testing (16). CDC and CMS also have been assessing the need to revise and update CLIA requirements for proficiency testing programs and laboratories, taking into consideration the need for improved performance evaluation for laboratories that perform genetic testing (37).

Studies and reports since 1997 have revealed a broad range of concerns related to molecular genetic testing for heritable diseases and conditions, including safe and effective translation of research findings into patient testing, the quality of test performance and results interpretation, appropriate use of testing information and services in health management and patient care, the adequacy of quality assurance measures, and concerns involving the ethical, legal, economic, and social aspects of molecular genetic testing (1,9,22,38,39). Some of these concerns are indicative of the areas of laboratory practice that are in need of improvement, such as performance establishment and verification, proficiency testing, personnel qualifications and training, and results reporting (1,9,11,22,39).

Studies have indicated that although error rates associated with different areas of laboratory testing vary (40), the overall distribution of errors reported in the preanalytic, analytic, and postanalytic phases of the testing process are similar for many testing areas, including molecular genetic testing (9,11,39,40). The preanalytic phase encompasses test selection and ordering and specimen collection, processing, handling, and delivery to the testing site. The analytic phase includes selection of test methods, performance of test procedures, monitoring and verification of the accuracy and reliability of test results, and documentation of test findings. The postanalytic phase includes reporting test results and archiving records, reports, and tested specimens (41).

Studies have indicated that errors are more likely to occur during the preanalytic and postanalytic phases of the testing process than during the analytic phase, with most errors reported for the preanalytic phase (40,42--44). In the preanalytic phase, inappropriate selection of laboratory tests has been a significant source of errors (42,43). Misuse of laboratory services, such as unnecessary or inappropriate test requests, might lead to increased risk for medical errors, adverse patient outcome, and increased health-care costs (43). Although no study has determined the overall number of molecular genetic tests performed that could be considered unwarranted or unnecessary, a study of the use and interpretation of adenomatous polyposis coli gene (APC) testing for familial adenomatous polyposis and other heritable conditions associated with colonic polyposis indicated that 17% of the cases evaluated did not have valid indications for testing (22).

Although data are limited, studies also indicate that improvements are needed in the analytic phase of molecular genetic testing. A study of the frequency and severity of errors associated with DNA-based genetic testing revealed that errors related to specimen handling in the laboratory and other analytic steps ranged from 0.06% to 0.12% of approximately 92,000 tests evaluated (39). A subsequent meta-analysis indicated that these self-reported error rates were comparable to those detected in nongenetic laboratory testing (40). An analysis of performance data from the CAP molecular genetic survey program during 1995--2000 estimated the overall error rate for cystic fibrosis mutation analysis to be 1.5%, of which approximately 50% of the errors occurred during the analytic or postanalytic phases of testing (45). Unrecognized sequence variations or polymorphisms also could affect the ability of molecular genetic tests to detect or distinguish the genotypes being analyzed, leading to false-positive or false-negative test results. Such problems have been reported for some commonly performed genetic tests such as cystic fibrosis mutation analysis and testing for HFE-associated hereditary hemochromatosis (46,47).

The postanalytic phase of molecular genetic testing involves analysis of test results, preparation of test reports, and results reporting. The study on the use of the APC gene testing and interpretation of test results indicated that lack of awareness among health-care providers of APC test limitations was a primary reason for misinterpretation of test results (22). In a study assessing the comprehensiveness and usefulness of reports for cystic fibrosis and factor V Leiden thrombophilia testing, physicians in many medical specialties considered reports that included information beyond that specified by the general CLIA test report requirements to be more informative and useful than test reports that only met CLIA requirements; additional information included patient race/ethnicity, clinical history, reasons for test referral, test methodology, recommendations for follow-up testing, implications for family members, and suggestions for genetic counseling (48). Consistent with these findings, international guidelines for quality assurance in molecular genetic testing recommend that molecular genetic test reports be accurate, concise, and comprehensive and communicate all essential information to enable effective decision-making by patients and health care professionals (49).

Proficiency testing is a well-established practice for monitoring and improving the quality of laboratory testing (50,51) and is a key component of the external quality assessment process. Studies have indicated that using proficiency testing samples that resemble actual patient specimens could improve monitoring of laboratory performance (50,52--54). Participation in proficiency testing has helped laboratories reduce analytic deficiencies, improve testing procedures, and take steps to prevent future errors (55--59).

CLIA regulations have not yet included proficiency testing requirements for molecular genetic tests. Laboratories that perform molecular genetic testing must meet the general CLIA requirement to verify, at least twice annually, the accuracy of the genetic tests they perform (493.1236[c]) (36). Laboratories may participate in available proficiency testing programs for the genetic tests they perform to meet this CLIA alternative performance assessment requirement. Proficiency testing participation correlates significantly with the quality assurance measures in place among laboratories that perform molecular genetic testing (9,10). Because proficiency testing is a rigorous external assessment for laboratory performance, in 2008, SACGHS recommended that proficiency testing participation be required for all molecular genetic tests for which proficiency testing programs are available (1). Formal molecular genetic proficiency testing programs are available only for a limited number of tests for heritable diseases and conditions; in addition, the samples provided often are purified DNA, which do not typically require performance of all steps of the testing process, such as nucleic acid extraction and preparation (60). For many genetic conditions that are either rare or for which testing is performed by one or a few laboratories, substantial challenges in developing formal proficiency testing programs have been recognized (1).

Development of effective alternative performance assessment approaches to proficiency testing is essential for ensuring the quality of molecular genetic testing (1). Professional guidelines have been developed for laboratories to evaluate and monitor test performance when proficiency testing programs are not available (61). However, reports of the CAP molecular pathology on-site inspections indicate that deficiencies related to participation in interlaboratory comparison or alternative performance assessment are among the most frequently identified deficiencies, accounting for 3.9% of all deficiencies cited (62).

The ability of a test to diagnose or predict risk for a particular health condition is the test's clinical validity, which often is measured by clinical (or diagnostic) sensitivity, clinical (or diagnostic) specificity, and predictive values of the test for a given health condition. Clinical validity can be influenced by factors such as the prevalence of the disease or health condition, penetrance (proportion of persons with a mutation causing a particular disorder who exhibit clinical symptoms of the disorder), and modifiers (genetic or environmental factors that might affect the variability of signs or symptoms that occur with a phenotype of a genetic alteration). For genetic tests, clinical validity refers to the ability of a test to detect or predict the presence or absence of a particular disease or phenotype and often corresponds to associations between genotypes and phenotypes (1,28,63--69). The usefulness of a test in clinical practice, referred to as clinical utility, involves identifying the outcomes associated with specific test results (28). Clinical validity and clinical utility should be assessed individually for each genetic test because the implications might vary depending on the health condition and population being tested (38).

As advances in genomic research and technology result in rapid development of new genetic tests, concerns have been raised that certain tests, particularly predictive genetic tests, could become available without adequate assessment of their validity, benefits, and utility. Consequently, health professionals and consumers might not be able to make a fully informed decision about whether or how to use these tests. In 1997, a task force formed by a National Institutes of Health (NIH)--Department of Energy workgroup recommended that laboratories that perform patient testing establish clinical validity for the genetic tests they develop before offering them for patient testing and carefully review and document evidence of test validity if the test has been developed elsewhere (70). This recommendation was later included in a report of the Secretary's Advisory Committee on Genetic Testing (SACGT), which was established in 1998 to advise HHS on medical, scientific, ethical, legal, and social concerns raised by the development and use of genetic tests (38).

Public concerns about inadequate knowledge or documentation of the clinical validity of certain genetic tests were also recognized by SACGHS, the advisory committee that was established by HHS in 2002 to supersede SACGT (1). SACGHS recommended the development and support of sustainable public-private collaborations to fill the gaps in knowledge of the analytic validity, clinical validity, clinical utility, economic value, and population health impact of molecular genetic tests (1). Collaborative efforts that have been recognized include the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) program, a CDC initiative to establish and evaluate a systematic, evidence-based process for assessing genetic tests and other applications of genomic technology in transition from research to clinical practice and public health (71), and the Collaboration, Education, and Test Translation (CETT) Program, which is overseen by the NIH Office of Rare Diseases to promote the effective transition of potential genetic tests for rare diseases from research settings into clinical settings (72).

The increase in direct-to-consumer (DTC) genetic testing (i.e., genetic tests offered directly to consumers with no health-care provider involvement) has raised concerns about the potential risks or misuses of certain genetic tests (73). As of October 2008, consumers could directly order laboratory tests in 27 states; in another 10 states, consumer-ordered tests are allowed under defined circumstances (74). As DTC genetic tests become increasingly available, various genetic profile tests have been marketed directly to the public that claim to answer questions regarding cardiovascular risks, drug metabolism, dietary arrangements, and lifestyles (73). In addition, DTC advertisements have caused a substantial increase in the demand for molecular genetic tests, such as those for hereditary breast and ovarian cancers (75,76). Although allowing easy access to the testing services, DTC genetic testing has raised concerns about the potential for inadequate pretest decision-making, misunderstanding of test results, access to tests of questionable clinical value, lack of necessary follow-up, and unexpected additional responsibilities for primary care physicians (77--80). Both the government and professional organizations have developed educational materials that provide guidance to consumers, laboratories, genetics professionals, and professional organizations regarding DTC genetic tests (80--82).

Studies indicate that qualifications of laboratory personnel, including training and experience, are critical for ensuring quality performance of genetic testing, because human error has the greatest potential influence on the quality of laboratory test results (9,83,84). A study of laboratories in the United States that perform molecular genetic testing suggested that laboratory adherence to voluntary quality standards and guidelines for genetic testing was significantly associated with laboratories directed or supervised by persons with board certification in medical genetics (9). Results of an international survey revealed a similar correlation between the quality assurance practices of a molecular genetic testing laboratory and the formal training of the laboratory director (10). Overall, the concerns recognized in publications and documented cases support the need to have trained, qualified personnel at all levels to ensure the quality of all phases of the genetic testing process.

To monitor and assess the scope and growth of molecular genetic testing in the United States, data were collected and analyzed from scientific articles, government reports, the CMS CLIA database, information from state programs, studies by professional groups, publicly available directories and databases of laboratories and laboratory testing, industry reports, and CDC studies (1--3,5,6,9,29,38,83,85--88). To evaluate factors in molecular genetic testing that might affect testing quality and to identify areas that would benefit from quality assurance guidelines, various documents were considered, including professional practice guidelines, CAP laboratory accreditation checklists, CLSI guidelines, state requirements, and international guidelines and standards (12--15,49,61,89--95).

Since 1997, CLIAC has provided HHS with recommendations on approaches needed to ensure the quality of genetic testing (37). At the February 2007 CLIAC meeting, CLIAC asked CDC and CMS to clarify critical concerns in genetic testing oversight and to provide a status report at the subsequent CLIAC meeting. At the September 2007 CLIAC meeting, CDC presented an overview of the regulatory oversight and voluntary measures for quality assurance of genetic testing and described a plan to develop and publish educational material on good laboratory practices. CDC solicited CLIAC recommendations to address concerns that presented particular challenges related to genetic testing oversight, including establishment and verification of performance specifications, control procedures for molecular amplification assays, proficiency testing, genetic test reports, personnel competency assessment, and the definition of genetic tests. CLIAC recommended convening a workgroup of experts in genetic testing to consider these concerns and provide input for CLIAC deliberation.

The CLIAC Genetic Testing Good Laboratory Practices Workgroup was formed. The workgroup conducted a series of meetings on the scope of laboratory practice recommendations needed for genetic testing and suggested that recommendations first be developed for molecular genetic testing for heritable diseases and conditions. The workgroup evaluated good laboratory practices for all phases of the genetic testing process after reviewing professional guidelines, regulatory and voluntary standards, accreditation checklists, international standards and guidelines, and other documents that provided general or specific quality standards applicable to molecular genetic testing for heritable diseases and conditions (1,12--15,36,41,49,61,80,82,91--109). The workgroup also reviewed information on the HHS-approved and other certification boards for laboratory personnel and the number of persons certified in each of the specialties for which certification is available (110--118). Workgroup suggestions were reported to CLIAC at the September 2008 committee meeting. The CLIAC recommendations were formed on the basis of the workgroup report and additional CLIAC recommendations. The committee recommended that CDC include the CLIAC-recommended good laboratory practices for molecular genetic testing in the planned publication. Summaries of CLIAC meetings and CLIAC recommendations are available (37).

The following recommended good laboratory practices are for areas of molecular genetic testing for heritable diseases and conditions in need of guidelines for complying with existing CLIA requirements or in need of additional quality assurance measures. These recommendations are not intended to encompass the entire realm of laboratory practice; they are meant to provide guidelines for specific quality concerns in the performance and delivery of laboratory services for molecular genetic testing for heritable diseases and conditions.

These recommendations address laboratory practices for the total testing process, including the preanalytic, analytic, and postanalytic phases of molecular genetic testing. The recommendations for the preanalytic phase include guidelines for laboratory responsibilities for providing information to users of laboratory services, informed consent, test requests, specimen submission and handling, test referrals, and preanalytic systems assessment. The recommendations for the analytic phase include guidelines for establishment and verification of performance specifications, quality control procedures, proficiency testing, and alternative performance assessment. The recommendations for the postanalytic phase include guidelines for test reports, retention of records and reports, and specimen retention. The recommendations also address responsibilities of laboratories regarding authorized persons, confidentiality of patient information and test results, personnel competency, factors to consider before introducing molecular genetic testing or offering new molecular genetic tests, and the potential benefits of the quality management system approach in molecular genetic testing. Recommendations are provided in relation to applicable provisions in the CLIA regulations and, when necessary, are followed by a description of how the recommended practices can be used to improve quality assurance and quality assessment for molecular genetic testing. A list of terms and abbreviations used in this report also is provided (Appendix A).

Laboratories are responsible for providing information regarding the molecular genetic tests they perform to users of their services; users include authorized persons under applicable state law, health-care professionals, patients, referring laboratories, and payers of laboratory services. Laboratories should review the genetic tests they perform and the procedures they use to provide and update the recommended test information that follows. At a minimum, laboratories should ensure that the test information is available from accessible sources such as websites, service directories, information pamphlets or brochures, newsletters, instructions for specimen submission, and test request forms. Laboratories that already provide the information from these sources should continue to do so. However, laboratories also might decide to provide the information more directly to their users (e.g., by telephone, e-mail, or in an in-person meeting) and should determine the situations in which such direct communication is necessary. The complexity of language used should be appropriate for the particular laboratory user groups (e.g., for patients, plain language understandable by the general public).

Test selection, test performance, and specimen submission. Laboratories should provide information regarding the molecular genetic tests they perform to users of their services to facilitate appropriate test selection and requests, specimen handling and submission, and patient care. Each laboratory that performs molecular genetic testing for heritable diseases and conditions should provide the following information to its users:

--- Intended use of the test, including the nucleic acid target of the test (e.g., genes, sequences, mutations, or polymorphisms), the purpose of testing (e.g., diagnostic, preconception, or predictive), and the recommended patient populations

--- Indications for testing

--- Test method to be used, presented in user-friendly language in relation to the performance specifications and the limitations of the test (with Current Procedural Terminology [CPT] codes included when appropriate)

--- Specifications of applicable performance characteristics, including information on analytic validity and clinical validity

--- Limitations of the test

--- Whether testing is performed with an FDA-approved or FDA-cleared test system, with a laboratory-developed test or test system that is not approved or cleared by FDA, or with an investigational test under FDA oversight

Cost. When possible and practical, laboratories should provide users with information on the charges for molecular genetic tests being performed. Estimating the expenses that a patient might incur from a particular genetic test might be difficult for certain laboratories and providers because fee schedules of individual laboratories can vary depending on the health-care payment policy selections of each patient. However, advising the patient and family members of the financial implications of the tests, whenever possible, facilitates informed decision-making.

Discussion. Under CLIA, laboratories are required to develop and follow written policies and procedures for specimen submission and handling, specimen referral, and test requests (42 CFR 493.1241 and 1242). Laboratories must ensure positive identification and optimum integrity of specimens from the time of collection or receipt through the completion of testing and reporting of test results (42 CFR 493.1232). In addition, laboratories that perform nonwaived testing must ensure that a qualified clinical consultant is available to assist laboratory clients with ordering tests appropriate for meeting clinical expectations (42 CFR 493.1457[b]). The recommended laboratory practices in this report describe laboratory responsibilities for ensuring appropriate test requests and specimen submission for the molecular genetic tests they perform, in addition to laboratory responsibilities for meeting CLIA requirements. The recommendations emphasize the role of laboratories in providing specific information needed by users before decisions are made regarding test selection and ordering, based on consideration of several factors.

First, molecular genetic tests for heritable diseases and conditions are being rapidly developed and increasingly used in health-care settings. Users of laboratory services need the ability to easily access information regarding the intended use, performance specifications, and limitations of the molecular genetic tests a laboratory offers to determine appropriate testing for specific patient conditions.

Second, many molecular genetic tests are performed using laboratory-developed tests or test systems. The performance specifications and limitations of the testing might vary among laboratories, even for the same disease or condition, depending on the specific procedures used. Users of laboratory services who are not provided information related to the appropriateness of the tests being considered might select tests that are not indicated or cannot meet clinical expectations.

Third, for many heritable diseases and conditions, test performance and interpretation of test results require information regarding patient race/ethnicity, family history, and other pertinent clinical and laboratory information. Informing users before tests are ordered of the specific patient information needed by the laboratory should facilitate test requests and allow prompt initiation of appropriate testing procedures and accurate interpretation of test results.

Finally, providing information to users on performance specifications and limitations of tests before test selection and ordering prepares users of laboratory services for understanding test results and implications. CLIA test report requirements (42 CFR 493.1291[e]) indicate that laboratories are required to provide users of their services, on request, with information on laboratory test methods and the performance specifications the laboratory has established or verified for the tests. However, for molecular genetic tests for heritable diseases and conditions, laboratories should provide test performance information to users before test selection and ordering, rather than waiting for a request after the test has been performed. The information provided in the preanalytic phase must be consistent with information included on test reports.

Providing molecular genetic testing information to users before tests are selected and ordered should improve test requests and specimen submission and might reduce unnecessary or unwarranted testing. The recommended practices also might increase informed decision-making, improve interpretation of results, and improve patient outcome.

A person who provides informed consent voluntarily confirms a willingness to undergo a particular test, after having been informed of all aspects of the test that are relevant to the patient's decision (49). Informed consent for genetic testing or specific types of genetic tests is required by law in certain states; as of June 2008, 12 states required that informed consent be obtained before a genetic test is requested or performed (119). In addition, certain states (e.g., Massachusetts, Michigan, Nebraska, New York, and South Dakota) have included required informed consent components in their statutes [97,120--123]) (Appendix B). These state statutes can be used as examples for laboratories in other states that are developing specific informed consent forms. Professional organizations recommend that informed consent be obtained for testing for many inherited genetic conditions (12,13). CLIA regulations have no requirements for laboratory documentation of informed consent for requested tests; however, medical decisions for patient diagnosis or treatment should be based on informed decision-making (124). Regardless of whether informed consent is required, laboratories that perform molecular genetic tests for heritable diseases and conditions should be responsible for providing users with the information necessary to make informed decisions.

Informed consent is in the purview of the practice of medicine; the persons authorized to order the tests are responsible for obtaining the appropriate level of informed consent (67). Unless mandated by state or local requirements, obtaining informed consent before performing a test generally is not considered a laboratory responsibility. For molecular genetic testing for heritable diseases and conditions, not all tests require written patient consent before testing (125). However, when informed consent for patient testing is recommended or required by law or other applicable requirements as a method for documenting the process and outcome of informed decision-making, laboratories should ensure that certain practices are followed:

Laboratories should refer to professional guidelines for additional information regarding informed consent for molecular genetic tests and should consider available models when developing the content, format, and procedures for documentation of patient consent.

CLIA requirements (42 CFR 493.1241[c]) specify that laboratories that perform nonwaived testing must ensure that the test request solicits the following information: 1) the name and address or other suitable identifiers of the authorized person requesting the test and (if applicable) the person responsible for using the test results, or the name and address of the laboratory submitting the specimen, including (if applicable) a contact person to enable reporting of imminently life-threatening laboratory results or critical values; 2) patient name or a unique patient identifier; 3) sex and either age or date of birth of the patient; 4) the tests to be performed; 5) the source of the specimen (if applicable); 6) the date and (if applicable) time of specimen collection; and 7) any additional information relevant and necessary for a specific test to ensure accurate and timely testing and reporting of results, including interpretation (if applicable). For molecular genetic testing for heritable diseases and conditions, laboratories must comply with these CLIA requirements and should solicit the following additional information on test requests:

Patient name and any other unique identifiers needed for testing. CLIA test request requirements indicate that laboratories must solicit patient names or unique patient identifiers on test requests (42 CFR 493.1241[c][2]). Laboratories that perform molecular genetic testing for heritable diseases and conditions should ensure that at least two unique identifiers are solicited on these test requests, which should include patient names, when possible, and any other unique identifiers needed to ensure patient identification. In certain situations (e.g., compatibility testing for which donor names are not always provided to the laboratory), an alternative unique identifier is appropriate.

Date of birth. CLIA requirements specify that test requests must solicit the sex and either age or date of birth of the patient (42 CFR 493.1241[c][3]). For molecular genetic testing for heritable diseases and conditions, patient date of birth is more informative than age and should be obtained when possible.

Indications for testing, relevant clinical and laboratory information, patient race/ethnicity, family history, and pedigree. Obtaining information on indications for testing, relevant clinical or laboratory information, patient racial/ethnic background, family history, and pedigree is critical for selecting appropriate test methods, determining the mutations or variants to be tested, interpreting test results, and timely reporting of test results. Genetic conditions often have different disease prevalences with various mutation frequencies and distributions among racial/ethnic groups. Unique, or private, mutations or genotypes might be present only in specific families or can be associated with founder effects (i.e., gene mutations observed in high frequency in a specific population because of the presence of the mutation in a single ancestor or small number of ancestors in the founding population). Family history and other relevant clinical or laboratory information are often important for determining whether the test requested might meet the clinical expectations, including the likelihood of identifying a disease-causing mutation. Specific race/ethnicity, family history, and other pertinent information to be solicited on a test request should be determined according to the specific disease or condition for which the patient is being tested. Laboratories should consider available guidelines for requesting and obtaining this additional information and determine circumstances in which more specific patient information is needed for particular genetic tests (126,127). Although this information is not specified in CLIA, the regulations provide laboratories the flexibility to determine and solicit relevant and necessary information for a specific test (42 CFR 493.1241[c][8]). The recommended test request components also are consistent with many voluntary professional and accreditation guidelines (12--14).

Documentation of informed consent. Methods for indicating and documenting informed consent on a test request might include a statement, text box, or check-off box on the test request form to be signed or checked by the test requestor; a separate form to be signed as part of the test request; or another method that complies with applicable requirements and adheres to professional guidelines. In addition, when state or local laws or regulations specify that patient consent must be obtained regarding the use of tested specimens for quality assurance or other purposes, the test request must include a way for the test requestor to indicate the decision of the patient. Laboratories also might determine that other situations merit documentation of consent before testing.

CLIA requires laboratories to establish and follow written policies and procedures for patient preparation, specimen collection, specimen labeling (including patient name or unique patient identifier and, when appropriate, specimen source), specimen storage and preservation, conditions for specimen transportation, specimen processing, specimen acceptability and rejection, and referral of specimens to another laboratory (42 CFR 493.1242). If a laboratory accepts a referral specimen, appropriate written instructions providing information on specimen handling and submission must be available to the laboratory clients. The following recommendations are intended to help laboratories that perform molecular genetic testing meet general CLIA requirements and to provide additional guidelines on quality assurance measures for specimen submission, handling, and referral for molecular genetic testing. Before test selection and ordering, laboratories that perform molecular genetic testing should provide their users with instructions on specimen collection, handling, transport, and submission. Information on appropriate collection, handling, and submission of specimens for molecular genetic tests should include the following:

Criteria for specimen acceptance or rejection. Laboratories should have written criteria for acceptance or rejection of specimens for the molecular genetic tests they perform and should promptly notify the authorized person when a specimen meets the rejection criteria and is determined to be unsuitable for testing. The criteria should include information on determining the existence of and addressing the following situations:

Retention and exchange of information throughout the testing process. Information on test requests and test reports is a particularly important component of the complex communication between genetic testing laboratories and their users. Laboratories should have policies and procedures in place to ensure that information needed for selection of appropriate test methods, test performance, and results interpretation is retained throughout the entire molecular genetic testing process. This recommendation is based on CLIAC recognition of instances in which information on test requests or test reports was removed by electronic or other information systems during specimen submission, results reporting, or test referral. CLIA requires laboratories to ensure the accuracy of test request or authorization information when transcribing or entering the information into a record system or a laboratory information system (42 CFR 493.1241[e]). For molecular genetic tests, information on test requests and test reports should be retained accurately and completely throughout the testing process.

Specimen referral. CLIA requires laboratories to refer specimens for any type of patient testing to CLIA-certified laboratories or laboratories that meet equivalent requirements as determined by CMS (42 CFR 493.1242[c]). Examples of laboratories that meet equivalent requirements include Department of Veterans Affairs laboratories, Department of Defense laboratories, and laboratories in CLIA-exempt states.

Laboratories must have written policies and procedures for assessing and correcting problems identified in test requests, specimen submission, and other preanalytic steps of molecular genetic testing (42 CFR 493.1249). The preanalytic systems assessment for molecular genetic testing should include the following practices:

CLIA requires laboratories to establish or verify the analytic performance of all nonwaived tests and test systems before introducing them for patient testing and to determine the calibration and control procedures of tests based on the performance specifications verified or established. Before reporting patient test results, each laboratory that introduces an unmodified, FDA-cleared or FDA-approved test system must 1) demonstrate that the manufacturer-established performance specifications for accuracy, precision, and reportable range of test results can be reproduced and 2) verify that the manufacturer-provided reference intervals (or normal values) are appropriate for the laboratory patient population (42 CFR 493.1253). Laboratories are subject to more stringent requirements when introducing 1) FDA-cleared or FDA-approved test systems that have been modified by the laboratory, 2) laboratory-developed tests or test systems that are not subject to FDA clearance or approval (e.g., standardized methods and textbook procedures), or 3) test systems with no manufacturer-provided performance specifications. In these instances, before reporting patient test results, laboratories must conduct more extensive procedures to establish applicable performance specifications for accuracy, precision, analytic sensitivity, analytic specificity; reportable range of test results; reference intervals, or normal values; and other performance characteristics required for test performance.

Although laboratories that perform molecular genetic testing for heritable diseases and conditions must comply with these general CLIA requirements, additional guidelines are needed to assist with establishment and verification of performance specifications for these tests. The recommended laboratory practices that follow are primarily intended to provide specific guidelines for establishing performance specifications for laboratory-developed molecular genetic tests to ensure valid and reliable test performance and interpretation of results. The recommendations also might be used by laboratories to verify performance specifications of unmodified FDA-cleared or FDA-approved molecular genetic test systems to be introduced for patient testing.

Factors that should be considered when developing performance specifications for molecular genetic tests include the intended use of the test; target genes, sequences, and mutations; intended patient populations; test methods; and samples to be used (99). The following five steps should be considered general principles for establishing performance specifications of each new molecular genetic test:

Samples for establishment of performance specifications. Establishment of performance specifications should be based on an adequate number, type, and variety of samples to ensure that test results can be interpreted for specific patient conditions and that the limitations of the testing and test results are known. When selecting samples, the following factors should be considered:

Analytic performance specifications. Laboratories should determine performance specifications for all of the following analytic performance characteristics for molecular genetic tests that are not cleared or approved by FDA before introducing the tests for patient testing:

Accuracy. Accuracy is commonly defined as "closeness of the agreement between the result of a measurement and a true value of the measurand" (128). For qualitative molecular genetic tests, laboratories are responsible for verifying or establishing the accuracy of the method used to identify the presence or absence of the analytes being evaluated (e.g., mutations, variants, or other targeted nucleic acids). Accuracy might be assessed by testing reference materials, comparing test results against results of a reference method, comparing split-sample results with results obtained from a method shown to provide clinically valid results, or correlating research results with the clinical presentation when establishing a test system for a new analyte, such as a newly identified disease gene (96).

Precision. Precision is defined as "closeness of agreement between independent test results obtained under stipulated conditions" (129). Precision is commonly determined by assessing repeatability (i.e., closeness of agreement between independent test results for the same measurand under the same conditions) and reproducibility (i.e., closeness of agreement between independent test results for the same measurand under changed conditions). Precision can be verified or established by assessing day-to-day, run-to-run, and within-run variation (as well as operator variance) by repeat testing of known patient samples, quality control materials, or calibration materials over time (96).

Analytic sensitivity. Practice guidelines vary in their definitions of analytic sensitivity; certain guidelines consider analytic sensitivity to be the ability of an assay to detect a given analyte, or the lower limit of detection (LOD) (93), whereas guidelines for molecular genetic testing for heritable diseases consider analytic sensitivity to be "the proportion of biological samples that have a positive test result or known mutation and that are correctly classified as positive" (12). However, determining the LOD of a molecular genetic test or test system is often needed as part of the performance establishment and verification (93). To avoid potential confusion among users and the general public in understanding the test performance and test results, laboratories should review and follow applicable professional guidelines before testing is introduced and ensure the guidelines are followed consistently throughout performance establishment and verification and during subsequent patient testing. Analytic sensitivity should be determined for each molecular genetic test before the test is used for patient testing.

Analytic specificity. Analytic specificity is generally defined as the ability of a test method to determine only the target analytes to be detected or measured and not the interfering substances that might affect laboratory testing. Interfering substances include factors associated with specimens (e.g., specimen hemolysis, anticoagulant, lipemia, and turbidity) and factors associated with patients (e.g., clinical conditions, disease states, and medications) (96). Laboratories must document information regarding interfering substances and should use product information, literature, or the laboratory's own testing (96). Accepted practice guidelines for molecular genetic testing, such as those developed by ACMG, CAP, and CLSI, define analytic specificity as the ability of a test to distinguish the target sequences, alleles, or mutations from other sequences or alleles in the specimen or genome being analyzed (12--14). The guidelines also address documentation and determination of common interfering substances specific for molecular detection (e.g., homologous sequences, contaminants, and other exogenous or endogenous substances) (12--14). Laboratories should adhere to these specific guidelines in establishing or verifying analytic specificity for each of their molecular genetic tests.

Reportable range of test results. As defined by CLIA, the reportable range of test results is "the span of test result values over which the laboratory can establish or verify the accuracy of the instrument or test system measurement response" (36). The reportable range of patient test results can be established or verified by assaying low and high calibration materials or control materials or by evaluating known samples of abnormally high and low values (96). For example, laboratories should assay quality control or reference materials, or known normal samples, and samples containing mutations to be detected for targeted mutation analyses. For analysis of trinucleotide repeats, laboratories should include samples representing the full range of expected allele lengths (130).

Reference range, or reference interval (i.e., normal values). As defined by CLIA, a reference range, or reference interval, is "the range of test values expected for a designated population of persons (e.g., 95% of persons that are presumed to be healthy [or normal])" (36). The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provides general guidelines regarding the use of manufacturer-provided or published reference ranges appropriate for the patient population and evaluation of an appropriate number of samples to verify manufacturer claims or published reference ranges (96). For all laboratory-developed tests, the laboratory is responsible for establishing the reference range appropriate for the laboratory patient population (including demographic variables such as age and sex) and specimen types (96). For molecular genetic tests for heritable diseases and conditions, normal values might refer to normal alleles in targeted mutation analyses or the reference sequences for sequencing assays. Laboratories should be aware that advances in knowledge and testing technology might affect the recognition and documentation of normal sequences and should keep an updated database for the molecular genetic tests they perform.

Quality control procedures. CLIA requires laboratories to determine the calibration and control procedures for nonwaived tests or test systems on the basis of the verification or establishment of performance specifications for the tests (42 CFR 493.1253[b][3]). Laboratories that perform molecular genetic tests must meet these requirements and, for every molecular genetic test to be introduced for patient testing, should consider the recommended quality control practices.

Documentation of information on clinical validity. Laboratories should ensure that the molecular genetic tests they perform are clinically usable and can be interpreted for specific patient situations. Laboratory responsibilities for clinical validity include the following:

Although CLIA regulations do not include validation of clinical performance specifications of new tests or test systems, laboratories are required to ensure that the tests being performed meet clinical expectations. For tests of high complexity, such as molecular genetic tests, laboratory directors and technical supervisors are responsible for ensuring that the testing method is appropriate for the clinical use of the test results and can provide the quality of results needed for patient care (36). Laboratory directors and clinical consultants must ensure laboratory consultations are available for laboratory clients regarding the appropriateness of the tests ordered and interpretation of test results (36). Documentation of available clinical validity information helps laboratories that perform molecular genetic testing to fulfill their responsibilities for consulting with health-care professionals and other users of laboratory services, especially regarding tests that evaluate germline mutations or variants that might be performed only once during a patient's lifetime.

Establishing clinical validity is a continuous process and might require extended studies and involvement of many disciplines (38). The recommendations in this report emphasize the responsibility of laboratories that perform molecular genetic testing to document available information from medical and scientific research studies on the intended patient populations to be able to perform testing and provide results interpretation appropriate for specific clinical contexts. Laboratory directors are responsible for using professional judgment to evaluate the results of such studies as applied to newly discovered gene targets, especially those of a predictive or incompletely penetrant nature, in considering potential new tests. The recommendations in this report are consistent with the voluntary professional and accreditation guidelines of ACMG, CLSI, and CAP for molecular genetic testing (12--14,93,94).

General quality control practices. The analytic phase of molecular genetic testing often includes the following steps: specimen processing; nucleic acid extraction, preparation, and assessment; enzymatic reaction or amplification; analyte detection; and recording of test results. Laboratories that perform molecular genetic testing must meet the general CLIA requirements for nonwaived testing (42 CFR 493.1256) (36), including the following applicable quality control requirements:

--- At least two control materials of different concentrations for each quantitative procedure

--- A negative control material and a positive control material for each qualitative procedure

--- A negative control material and a control material with graded or titered reactivity, respectively, for each test procedure producing graded or titered results

--- Two control materials, including one that is capable of detecting errors in the extraction process, for each test system that has an extraction phase

--- Two control materials for each molecular amplification procedure and, if reaction inhibition is a substantial source of false-negative results, a control material capable of detecting the inhibition

Specific quality control practices. Specific quality control practices are necessary for ensuring the quality of molecular genetic test performance. The following recommendations include specific guidelines for meeting the general CLIA quality control requirements and additional measures that are more stringent or explicit than the CLIA requirements for monitoring and ensuring the quality of the molecular genetic testing process:

Alternative control procedures. Ideally, laboratories should use control materials to monitor the entire testing process, but such materials are not always practical or available. Appropriate alternative control procedures depend on the specific test and the control materials needed. Following are examples of accepted alternative control procedures when control materials are not available:

The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provides general guidelines for alternative control procedures and encourages laboratories to use multiple mechanisms for ensuring testing quality (96). Following are examples of procedures that, when applicable, should be followed by laboratories that perform molecular genetic testing:

Unidirectional workflow for molecular amplification procedures. CLIA requires laboratories to have procedures in place to monitor and minimize contamination during thetesting process and to ensure a unidirectional workflow for amplification procedures that are not contained in closed systems (42 CFR 493.1101) (36). In this context, a closed system is a test system designed to be fully integrated and automated to purify, concentrate, amplify, detect, and identify targeted nucleic acid sequences. Such a modular system generates test results directly from unprocessed samples without manipulation or handling by the user; the system does not pose a risk for cross-contamination because amplicon-containing tubes and compartments reamain completely closed during and after the testing process. For example, according to CLIA regulations, an FDA-cleared or FDA-approved test system that contains amplification and detection steps in sealed tubes that are never opened or reopened during or after the testing process and that is used as provided by the manufacturer (i.e., without any modifications) is considered a closed system.

The requirement for a unidirectional workflow, which includes having separate areas for specimen preparation, amplification, product detection, and reagent preparation, applies to any testing that involves molecular amplification procedures. The following recommendations provide more specific guidelines for laboratories that perform molecular genetic testing for heritable diseases and conditions using amplification procedures that are not in a closed system:

Laboratories should recognize that methods such as PCR amplification, whole genome amplification, or subcloning to prepare quality control materials might be a substantial source of laboratory contamination. These laboratories should have the following specific procedures to monitor, detect, and prevent cross-contamination:

These practices also should be considered by laboratories that purchase amplified materials for use as control materials, calibration materials, or competitors.

Proficiency testing is an important tool for assessing laboratory competence, evaluating the laboratory testing process, and providing education for the laboratory personnel. For certain analytes and testing specialties for which CLIA regulations specifically require proficiency testing, proficiency testing is provided by private-sector and state-operated programs that are approved by HHS because they meet CLIA standards (42 CFR Part 493). These approved programs also may provide proficiency testing for genetic tests and other tests that are not on the list of regulated analytes and specialties (131). Although the CLIA regulations do not have proficiency testing requirements specific for molecular genetic tests, laboratories that perform genetic tests must comply with the general requirements for alternative performance assessment for any test or analyte not specified as a regulated analyte to, at least twice annually, verify the accuracy of any genetic test or procedure they perform (42 CFR 493.1236[c]). Laboratories can meet this requirement by participating in available proficiency testing programs for the genetic tests they perform (132).

The following recommended practices provide more specific and stringent measures than the current CLIA requirements for performance assessment of molecular genetic testing. The recommendations should be considered by laboratories that perform molecular genetic testing to monitor and evaluate the ongoing quality of the testing they perform:

Proficiency testing samples. When possible, proficiency testing samples should resemble patient specimens; at a minimum, samples resembling patient specimens should be used for proficiency testing for the most common genetic tests. When proficiency testing samples are provided in the form of purified DNA, participating laboratories do not perform all the analytic steps that occur during the patient testing process (e.g., nucleic acid extraction and preparation). Such practical limitations should be recognized when assessing proficiency testing performance. Laboratories are encouraged to enroll in proficiency testing programs that examine the entire testing process, including the preanalytic, analytic, and postanalytic phases.

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Good Laboratory Practices for Molecular Genetic Testing ...

Promoting Safe and Effective Genetic Testing in the United States Table of Contents Final Report of the Task Force on Genetic Testing

The Task Force was created by the National Institutes of Health-Department of Energy Working Group on Ethical, Legal and Social Implications of Human Genome Research.

September 1997

EDITORS Neil A. Holtzman, M.D., MPH Michael S. Watson, Ph.D.

ACKNOWLEDGEMENTS

EXECUTIVE SUMMARY

ENSURING THE SAFETY AND EFFECTIVENESS OF NEW GENETIC TESTS

ENSURING THE QUALITY OF LABORATORIES PERFORMING GENETIC TESTS

IMPROVING PROVIDERS' UNDERSTANDINGS OF GENETIC TESTING

GENETIC TESTING FOR RARE INHERITED DISORDERS

Chapter 1: INTRODUCTION

Chapter 2: ENSURING THE SAFETY AND EFFECTIVENESS OF NEW

Chapter 3: ENSURING THE QUALITY OF LABORATORIES PERFORMING GENETIC TESTS

Chapter 4: IMPROVING PROVIDERS' UNDERSTANDINGS OF GENETIC TESTING

Chapter 5: GENETIC TESTING FOR RARE INHERITED DISORDERS

Chapter 6: SUMMARY AND CONCLUSIONS

Appendix 1: Individuals and Organizations Who Provided Comments to the Task Force

Appendix 2: Response of the Task Force to the Food and Drug Administration's Proposed Rule on Analyte Specific Reagents

Appendix 3: State of the Art of Genetic Testing in the United States: Survey of Biotechnology Companies and Nonprofit Clinical Laboratories and Interviews of Selected Organizations

Appendix 4: Informational Materials about Genetic Tests

Appendix 5: The History of Newborn Phenylketonuria Screening in the U.S.

Appendix 6: Scientific Advances and Social Risks: Historical Perspectives of Genetic Screening Programs for Sickle Cell Disease, Tay-Sachs Disease, Neural Tube Defects and Down Syndrome, 1970-1997

GLOSSARY

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Last Reviewed: October 1, 2012

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Genetic Testing Report - genome.gov

Genetic testing looks for changes in a person's genes, chromosomes, or in the levels of certain important proteins.

Types of genetic tests include:

Once the DNA is separated out, scientists hunt for the gene along the DNA strand to see if it looks abnormal.

Another type of chromosome test, called FISH analysis (fluorescent in situ hybridization), can find small changes in the chromosomes that may be missed by the karyotype.

A newer type of chromosome test is called array CGH. It is a very sensitive test and can also find small changes in the chromosomes.

You may find companies offering home genetics testing kits on the Internet. These do-it-yourself test kits have not been proven to be accurate, and they may not even be testing for what they claim to be. You should talk to a genetics professional before you purchase or use this type of kit.

Sources:

"What Is Genetic Testing?" About Genetic Services. 19 Mar 2004. GeneTests. 21 Jan 2008

Burton, Jess, & Jon Turney. The Rough Guide to Genes & Cloning. London: Rough Guides Ltd., 2007.

"Frequently Asked Questions About Genetic Testing." Genetics and Genomics for Patients and the Public. 17 Dec 2007. National Human Genome Research Institute. 21 Jan 2008

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What Is Genetic Testing -- Information About Genetic Testing

Jewish Genetics: Abstracts and Summaries Part 1: Jewish Populations Last Update: April 26, 2016 Family TreeDNA: Genetic Testing Service Get genetically tested to discover your relationship to other families, other Jews, and other ethnic groups. Projects you might qualify to join include "Gesher Galicia - Jewish DNA Project", "JewishGen Belarus SIG DNA Project", "JewishGen Hungarian SIG DNA Project", "German Jewish Gersig DNA Project", "Jewish Frankfurt", "Sephardic Heritage DNA Project", "Jews of Rhodes Project", "The Jewish R1b Project", "Ashkenazi Levite R1a1", and "Jewish E Project". Order a DNA kit from FTDNA's headquarters in the USA This page collects Y-DNA and mtDNA data and analysis related to traditionally Rabbinical Jewish populations of the world, including: Ashkenazim (Jews of Northern and Eastern Europe) Sephardim (Spanish and Portuguese Jews) Mizrakhim (Middle Eastern Jews) Italkim (Italian Jews) Caucasian Mountain Jews (Dagestani and Azerbaijani Jews) Georgian Jews Indian Jews North African Jews Yemenite Jews Ethiopian Jews Steven Bray's study, 2010 Steven M. Bray, Jennifer G. Mulle, Anne F. Dodd, Ann E. Pulver, Stephen Wooding, and Stephen T. Warren. "Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population." Proceedings of the National Academy of Sciences of the United States of America (PNAS) 107:37 (September 14, 2010): pages 16222-16227. 471 unrelated Ashkenazim were genotyped. Among the comparative populations were 1705 continental Europeans and 1251 European-Americans. Also used for comparison were 3 Middle Eastern populations: Palestinian Arabs, Druze, and Bedouins. Abstract: "The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, yet it is still unclear how population bottlenecks, admixture, or positive selection contribute to its genetic structure. Here we analyzed a large AJ cohort and found higher linkage disequilibrium (LD) and identity-by-descent relative to Europeans, as expected for an isolate. However, paradoxically we also found higher genetic diversity, a sign of an older or more admixed population but not of a long-term isolate. Recent reports have reaffirmed that the AJ population has a common Middle Eastern origin with other Jewish Diaspora populations, but also suggest that the AJ population, compared with other Jews, has had the most European admixture. Our analysis indeed revealed higher European admixture than predicted from previous Y-chromosome analyses. Moreover, we also show that admixture directly correlates with high LD, suggesting that admixture has increased both genetic diversity and LD in the AJ population. Additionally, we applied extended haplotype tests to determine whether positive selection can account for the level of AJ-prevalent diseases. We identified genomic regions under selection that account for lactose and alcohol tolerance, and although we found evidence for positive selection at some AJ-prevalent disease loci, the higher incidence of the majority of these diseases is likely the result of genetic drift following a bottleneck. Thus, the AJ population shows evidence of past founding events; however, admixture and selection have also strongly influenced its current genetic makeup."

Excerpts from page 16222:

"The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, kept separate from its European neighbors by religious and cultural practices of endogamy (1). [...] Y-chromosome studies also indicate only a low amount of admixture with neighboring Europeans (8-10). [...] Consistent with recent reports (13, 20, 23-25), principal component analysis (PCA) using these combined datasets confirmed that the AJ individuals cluster distinctly from Europeans, aligning closest to Southern European populations along the first principal component, suggesting a more southern origin, and aligning with Central Europeans along the second, consistent with migration to this region (Fig. S1)."

Excerpts from page 16223:

"The higher diversity in the AJ population was paralleled by a lower inbreeding coefficient, F, indicating the AJ population is more outbred than Europeans, not inbred, as has long been assumed (P < 1e-7) (Table 1). The greater genetic variation among the AJ population was further confirmed using a pairwise identity-by-state (IBS) permutation test, which showed that average pairs of AJ individuals have significantly less genomewide IBS sharing than pairs of EA or Euro individuals (empirical P value < 0.05). Thus, our results show that the AJ population is more genetically diverse than Europeans. [...] We also compared the genome-wide haplotype structure between the AJ and European populations using a haplotype modeling algorithm (26), which models phased haplotypes as edges that pass through nodes at each SNP across the genome. The number of nodes in the model is correlated to the genetic variation, and the number of edges per node is inversely correlated to the haplotype length. Using this model, we found that the AJ population has a greater number of nodes (0.88-1.11% more) but fewer edges per node (3.82-4.76% fewer) compared with the Europeans (P < 1e-50) (Table S2), indicating both higher genetic variation and longer haplotypes in the AJ population, consistent with our previous results. [...] We removed SNPs in high LD and measured the mean heterozygosity per locus across the combined Middle Eastern populations (Bedouin, Palestinian, and Druze) and found that the AJ population had higher heterozygosity (0.3121 vs. 0.3053, P < 1e-23). Other reports showing no increased heterozygosity in the AJ relative to Middle Eastern populations (13, 22) were probably limited by lower AJ sample sizes, which our dataset overcomes. Thus, the increased genetic diversity and LD appear consistent with admixture rather than founding effects. [...] To evaluate admixture in the AJ population, we investigated the similarity between AJ and HGDP populations using PCA as well as a population clustering algorithm (32). Both analyses show that AJ individuals cluster between Middle Eastern and European populations (Fig. 2 A and B and Fig. S2A), corroborating other recent reports (13, 20, 22, 23, 25). Interestingly, our population clustering reveals that the AJ population shows an admixture pattern subtly more similar to Europeans than Middle Easterners (Fig. 2 A and C, Lower), while also verifying that the Ashkenazi Jews possess a unique genetic signature clearly distinguishing them from the other two regions (Fig. 2C, Upper). The fixation index, FST, calculated concurrently to the PCA, confirms that there is a closer relationship between the AJ and several European populations (Tuscans, Italians, and French) than between the AJ and Middle Eastern populations (Fig. S2B)."

Excerpts from pages 16223-16224:

"Although the proximity of the AJ and Italian populations could be explained by their admixture prior to the Ashkenazi settlement in Central Europe (13), it should be noted that different demographic models may potentially yield similar principal component projections (33); thus, it is also consistent that the projection of the AJ populations is primarily the outcome of admixture with || Central and Eastern European hosts that coincidentally shift them closer to Italians along principle component axes relative to Middle Easterners."

Excerpts from page 16224:

"We used the combined Palestinian and Druze populations to represent the Middle Eastern ancestor and tested three different European groups as the European ancestral population (SI Materials and Methods). Using these proxy ancestral populations, we calculated the amount of European admixture in the AJ population to be 35 to 55%. Previous estimates of admixture levels have varied widely depending on the chromosome or specific locus being considered (18), with studies of Y-chromosome haplogroups estimating from 5 to 23% European admixture (8, 9). Our higher estimate is in part a result of the use of different proxies for the Jewish ancestral population."

Excerpts from page 16226:

"Multiple studies have found that the 'lactase-persistence' allele at the LCT locus was selected for in Northern Europeans, with the selective sweep presumably occurring at the time of the domestication of cattle 2,000 to 20,000 y ago (42, 43). The absence of this allele in our data would suggest that the selective sweep was complete before the Ashkenazi establishment in Europe. Moreover, the prevalence of lactase deficiency in Ashkenazi Jews has been estimated at 60 to 80% (44), further corroborating the lack of selection for the LCT locus in the AJ population. [...] Intriguingly, the AJ population has long been known to have lower levels of alcoholism than other groups (16, 46), with one study showing that Jewish males have a 2.5-fold lower lifetime rate of alcohol abuse/dependence compared with non-Jews (47). [...] Our results, together with a recent study showing that variation in the ALDH2 promoter affects alcohol absorption in Jews (48), now suggest that genetic factors and selective pressure at the ALDH2 locus may have contributed to the low levels of alcoholism."

Quinn Eastman of Emory University with ScienceDaily staff. "Analysis of Ashkenazi Jewish Genomes Reveals Diversity, History." ScienceDaily (August 27, 2010). Excerpts:

"Common Genetic Threads Link Thousands of Years of Jewish Ancestry." ScienceDaily (June 4, 2010). Excerpts:

Razib Khan. "Genetics and the Jews." Discover Magazine - Gene Expression (June 6, 2010).

"Dienekes Pontikos". "Two Major Groups of Living Jews." dienekes.blogspot.com (June 3, 2010).

Alla Katsnelson. Jews worldwide share genetic ties: But analysis also reveals close links to Palestinians and Italians." Nature.com (June 3, 2010). Excerpts:

Sharon Begley. "The DNA of Abraham's Children." Newsweek Web Exclusive (June 3, 2010). Excerpts:

Andrea Anderson. "Study Points to Shared Genetic Patterns amongst Jewish Populations." GenomeWeb News (June 3, 2010). Excerpts:

Nicholas Wade. "In DNA, New Clues to Jewish Roots." The New York Times (May 14, 2002): F1 (col. 1). Excerpts:

Mark G. Thomas, Michael E. Weale, Abigail L. Jones, Martin Richards, Alice Smith, Nicola Redhead, Antonio Torroni, Rosaria Scozzari, Fiona Gratrix, Ayele Tarekegn, James F. Wilson, Cristian Capelli, Neil Bradman, and David B. Goldstein. "Founding Mothers of Jewish Communities: Geographically Separated Jewish Groups Were Independently Founded by Very Few Female Ancestors." The American Journal of Human Genetics 70:6 (June 2002): 1411-1420. The study collected mtDNA from about 600 Jews and non-Jews from around the world, including 78 Ashkenazic Jews and Georgians, Uzbeks, Germans, Berbers, Ethiopians, Arabs, etc. 17.9% of sampled Iraqi Jews have an mtDNA pattern known as U3, compared to 2.6% of Ashkenazic Jews, 0.9% of Moroccan Jews, 1.7% of ethnic Berbers, 1.1% of ethnic Germans, 0.0% of Iranian Jews, 0.0% of Georgian Jews, 0.0% of Bukharian Jews, 0.0% of Yemenite Jews, 0.0% of Ethiopian Jews, 0.0% of Indian Jews, 0.0% of Syrian Arabs, 0.0% of Georgians, 0.0% of Uzbeks, 0.0% of Yemeni Arabs, 0.0% of Ethiopians, 0.0% of Asian Indians, 0.0% of Israeli Arabs. (According to Vincent Macaulay, U3 is found also among some Turks, Iraqis, Caucasus tribes, Alpine Europeans, North Central Europeans, Kurds, Azerbaijanis, Eastern Mediterranean Europeans, Central Mediterranean Europeans, Western Mediterranean Europeans, and southeastern Europeans.) Another pattern, called Haplotype I, was found among 12.1% of Bukharan Jews, 2.6% of Ashkenazic Jews, 1.8% of Iraqi Jews, 1.3% of Iranian Jews, 1.1% of ethnic Germans, and 2.4% of ethnic Asian Indians, and none of the other groups among individuals tested. (According to Vincent Macaulay, Haplotype I is found also among some Northeastern Europeans, North Central Europeans, Caucasus tribes, Northwestern Europeans, and Scandinavians.) Yet another pattern, called Haplotype J1, was found among 12.5% of Iraqi Jews, 2.7% of Iranian Jews, 9.2% of Yemenite Jews, and 1.7% of Israeli Arabs, and none of the other groups among individuals tested. (According to Vincent Macaulay, Haplotype J1 is found also among some Iraqi Arabs, Bedouins, Palestinian Arabs, and Azerbaijanis.) To compare with Vincent Macaulay's research on mtDNA, visit Supplementary data from Richards et al. (2000). Abstract:

Martin Richards. "Beware the gene genies." The Guardian (February 21, 2003). Excerpts:

Page 1104: "It is worth mentioning that, on the basis of protein polymorphisms [which are not to be confused with Y chromosome polymorphisms], most Jewish populations cluster very closely with Iraqis (Livshits et al. 1991) that the latter, in turn, cluster very closely with Kurds (Cavalli-Sforza et al. 1994)."

At Table 1: Y Chromosome Haplogroup Distribution, it is indicated that 11.6 percent of Muslim Kurds and 9.4 percent of Bedouins also have Eu 19 chromosomes; hence, genetic drift rather than admixture with East Europeans may theoretically explain Eu 19's presence among Ashkenazi Jews. On the other hand, the origin of Eu 19 (now known as R1a1) is from eastern Europe thousands of years ago, perhaps the kurgan culture, and is found in much higher quantities among Slavs (like Sorbs, Belarusians, Ukrainians, and Poles) than any Middle Eastern tribe. For further data consult figure 1 in Ornella Semino, et al., "The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective," Science 290(5494) (Nov. 10, 2000): 1155-1159, as well as the 2003 Levite study referenced here. [Update added December 21, 2013: The Ashkenazic Levite variety of R1a1, sometimes called R1a-M582, was later found to be from an Iranian source rather than an East European source.]

In Figure 3 of Nebel et al.'s 2001 paper, it can be seen that while some Muslim Kurds possess the Cohen Modal Haplotype (at a frequency of 0.011), and even some Palestinian Arabs do (at a frequency of 0.021), more Muslim Kurds (0.095) have a haplotype that is a different Y DNA lineage, with a different allele number in one of the six microsatellite locis. Figure 3 is also interesting since it shows that 0.021 of Palestinian Arabs have the Cohen Modal Haplotype.

Judy Siegel. "Genetic evidence links Jews to their ancient tribe." Jerusalem Post (November 20, 2001). Excerpts:

"Study: North African, Iraqi Jewry nearly genetic twins." Jerusalem Post (November 19, 2001). Excerpts:

Tamara Traubman. "Study finds close genetic connection between Jews, Kurds." Ha'aretz (November 21, 2001). Excerpts:

"The Jewish World: This Week in Israel." Global Jewish Agenda (Jewish Agency for Israel, November 22, 2001). Excerpts:

"Evrei i kurdi - brat'ya po genam." MIGnews.com (Media International Group)

Max Gross. "'A Certain People': Study Confirms Deep Similarities Among Jews." Forward (August 16, 2002): B11. Excerpts:

"Jews and Arabs Share Recent Ancestry." Science Now (American Academy for the Advancement of Science, October 30, 2000). In the last sentence, it is admitted that European Jews mixed with groups residing in Europe. Excerpts:

Judy Siegel. "Experts find genetic Jewish-Arab link." Jerusalem Post (November 6, 2000). Despite its merits, this study uses a small sample size and an improbable set of test subjects. It is puzzling that the Northern Welsh were tested, because it's obvious that they are farther away from European Jews than Arabs. Why were they tested instead of the Serbs, Romanians, Italians, or Austrians - groups which, unlike the Welsh, had significant contact with Jews over the centuries? The selection of groups influences the results of any genetics study. Notice, however, that even according to this test, somewhere between 20 and 30 percent of the Jews do NOT have paternal-line ancestry from Israel. Excerpts:

Nicholas Wade. "Scientists Rough Out Humanity's 50,000-Year-Old Story." The New York Times (November 14, 2000). Excerpts:

Tamara Traubman. "A new study shows that the genetic makeup of Jews and Arabs is almost identical, and that both groups share common prehistoric ancestors." Ha'aretz (2000). Excerpts:

Nadine Epstein. "Family Matters: Funny, We Don't Look Jewish." Hadassah Magazine 82:5 (January 2001). Excerpts:

The assertion of Ostrer that Yiddish comes from Alsace and Rhineland has been debunked by solid research showing that Yiddish derives from Bavaria. Yiddish is clearly a form of High German, too, and not Low German. Epstein's article demonstrates a lack of linguistic knowledge.

Christopher Hitchens. "The Part-Jewish Question: Double the Pleasure or Twice the Pain? Of 'Semi-Semites' and Those Who Fear Them." Forward (January 26, 2001). Excerpts:

Hillel Halkin. "Wandering Jews -- and Their Genes." Commentary 110:2 (September 2000): 54-61. Excerpts:

Michael F. Hammer, Alan J. Redd, Elizabeth T. Wood, M. R. Bonner, Hamdi Jarjanazi, Tanya Karafet, A. Silvana Santachiara-Benerecetti, Ariella Oppenheim, Mark A. Jobling, Trefor Jenkins, Harry Ostrer, and Batsheva Bonn-Tamir. "Jewish and Middle Eastern non-Jewish Populations Share a Common Pool of Y-chromosome Biallelic Haplotypes.", PNAS 97:12 (June 6, 2000): 6769-6774. Summary:

According to Mark Jobling, "Jews are the genetic brothers of Palestinians, Lebanese, and Syrians".

Some revealing comments from the study's geneticists: Dina Kraft's May 9, 2000 article in the Associated Press quotes Hebrew University geneticist Howard Cedar who "said even though Y chromosomes are considered the best tool for tracing genetic heritage, researchers still don't know what the history is behind the variations. As a result, it is difficult to draw conclusions about genetic affinity.." The article also quotes Batsheva Bonne-Tamir, a Tel Aviv University geneticist, who "cautioned that the techniques were new and that until the human genome is mapped, it will be difficult to be certain about the conclusions."

"To say that Jews are somehow homogeneous across the entire diaspora is completely fallacious," says Ken Jacobs of the University of Montreal. "There is so much incredible genetic heterogeneity within the Jewish community -- any Jewish community." Jewish people simply don't exhibit the genetic homogeneity that [Kevin] MacDonald ascribes to them, Jacobs says. According to an Jacobs' views as summarized in an article in the New Times Los Angeles Online (April 20-26, 2000), "Witness For The Persecution" by Tony Ortega: "The only Jewish subgroup that does show some homogeneity -- descendants of the Cohanim, or priestly class -- makes up only about 2 percent of the Jewish population. Even within the Cohanim, and certainly within the rest of the Jewish people, there's a vast amount of genetic variation that simply contradicts MacDonald's most basic assertion that Jewish genetic sameness is a sign that Judaism is an evolutionary group strategy." In H-ANTISEMITISM, Ken Jacobs added: "Hammer's Jewish samples are heavily skewed towards the Kohanim... This is bound to reduce within-population variance in the Jewish sample... I pointed out solely that the data reported for the Jewish samples in the recent PNAS were remarkably similar to those published previously in studies of which Hammer was a co-author, the focus of which was the Kohanim... There is an ahistorical aspect to this work, as well as a serious conflation of genes, ethnicity, and religious belief. For example, as used in Hammer's study, the distinction between 'Syrian' and 'Palestinian' is based on fairly recent geo-political constructs that have little or no bearing on the patterns of gene flow in the region prior to 1000 CE.... In the original Lemba study, the complex of Y-chromosome genes was found in 45% of Kohanim among Ashkenazim, the percentage was 56% of Kohanim among the Sepharad, and 53% among the Buba clan of the Lemba. Among non-Kohanim the average Jewish % for this gene complex is less than 5%. One does not have to understand the lingo to see that there was inbreeding in one part of the dispersed Jewish communities and a certain level of outbreeding in the rest."

John Tooby, Professor of Anthropology at the University of California at Santa Barbara, is quoted in an article for Slate's "Culturebox" by Judith Shulevitz as saying: "The notion that Jews are a genetically distinct group doesn't make it on the basis of modern population genetics."

Chris Garifo. "U of A researcher heads breakthrough genetic study." Jewish News of Greater Phoenix 52:37 (May 19, 2000). Excerpts:

Ivan Oransky. "Tracing Mideast Roots Back to Isaac and Ishmael: Study of Y Chromosome Suggests a Common Ancestry for Jews and Arabs." The Forward (May 19, 2000). Excerpts:

Hillary Mayell. "Genetic Link Established Between Jews and Arabs." National Geographic News (May 10, 2000).

"Jews and Arabs are 'genetic brothers'." BBC News (May 10, 2000). Excerpts:

Nicholas Wade. "Y Chromosome Bears Witness to Story of the Jewish Diaspora." The New York Times (May 9, 2000): F4 (col. 1). Excerpts:

Norton Godoy. "Judeus e rabes: irmos." Isto (2000).

R. Highfield. "Jews, Arabs share ancestral link, study says." Calgary Herald (May 9, 2000): A19.

Marilynn Larkin. "Jewish-Arab affinities are gene-deep." The Lancet 355 (2000): 1699.

Maggie Fox. "Middle Eastern Roots: Shared Y Chromosome Illustrates Genetic Map of the Past." Reuters (May 9, 2000).

Joel J. Elias. "The Genetics of Modern Assyrians and their Relationship to Other People of the Middle East." Assyrian Health Network (July 20, 2000). Excerpts:

"North African Jews show slightly elevated membership in the k2 component prevalent in African populations. Similarly, in the Ashkenazi Jews, the proportion of the largely European k5 component is somewhat larger than that in the Sephardi Jews (23% vs. 16%). Within the Ashkenazi Jews from Eastern and Central Europe, we do see a signal (2.2%) of components common in East Asia that are less visible in Ashkenazi Jews from Western Europe or European Sephardi Jews (0.6%)."

Excerpts from page 882:

"Admixture demonstrates the connection of Ashkenazi, North African, and Sephardi Jews, with the most similar non-Jewish populations to Ashkenazi Jews being Mediterranean Europeans from Italy (Sicily, Abruzzo, Tuscany), Greece, and Cyprus. When subtracting the k5 component, which perhaps originates in Ashkenazi and Sephardi Jews from admixture with European hosts, the best matches for membership patterns of the Ashkenazi Jews shift to the Levant: Cypriots, Druze, Lebanese, and Samaritans. [...] Considering the IBD threshold of 3 Mb for shared segments, Ashkenazi Jews are expected to show no significant IBD sharing with any population from which they have been isolated for [approximately more than] 20 generations. [...] Ashkenazi Jews show significant IBD sharing only with Eastern Europeans, North African Jews, and Sephardi Jews."

Agence France-Presse. "Study confirms Jewish Middle East origins." Sydney Morning Herald, June 11, 2010. Excerpt:

Alla Katsnelson. "Genes link Jewish communities, take 2." Nature: The Great Beyond (June 9, 2010). Excerpt:

Razib Khan. "Genetics and the Jews (it's still complicated.)" Discover Magazine - Gene Expression (June 10, 2010). Excerpts:

Excerpts from the body of the article:

Martin Richards. "New information is discovered about the ancestry of Ashkenazi Jews." Press release released October 8, 2013. Excerpts:

Nicholas Wade. "Genes Suggest European Women at Root of Ashkenazi Family Tree." The New York Times (October 9, 2013). Excerpts:

Jon Entine. "Ashkenazi Jewish Women Descended Mostly from Italian Converts, New Study Asserts." Genetic Literacy Project (October 8, 2013). Excerpts:

Kate Yandell. "Genetic Roots of the Ashkenazi Jews." The Scientist Magazine (October 8, 2013). Excerpts:

Eva Fernndez, Alejandro Prez-Prez, Cristina Gamba, Eva Prats, Pedro Cuesta, Josep Anfruns, Miquel Molist, Eduardo Arroyo-Pardo, and Daniel Turbn. "Ancient DNA Analysis of 8000 B.C. Near Eastern Farmers Supports an Early Neolithic Pioneer Maritime Colonization of Mainland Europe through Cyprus and the Aegean Islands." PLoS Genetics 10:6 (June 5, 2014): e1004401. Some ancient skeletons from the "Pre-Pottery Neolithic B" ("PPNB") sites at Tell Halula and Tell Ramad in what's now Syria had the "K" mtDNA haplogroup. This PPNB population genetically clusters with the modern-day Ashkenazi Jews, Csng people, and the population of Cyprus, who all have high frequencies of "K". (Modern Syrians are in a different cluster.) The evidence weighs against Costa et al.'s interpretation that the "K" haplogroups that Ashkenazim possess reflect European ancestors rather than Middle Eastern ones. Fernndez et al. wrote:

Shai Carmi, Ethan Kochav, Ken Y. Hui, Xinmin Liu, James Xue, Fillan Grady, Saurav Guha, Kinnari Upadhyay, Semanti Mukherjee, B. Monica Bowen, Joseph Vijai, Ariel Darvasi, Kenneth Offit, Laurie J. Ozelius, Inga Peter, Judy H. Cho, Harry Ostrer, Gil Atzmon, Lorraine N. Clark, Todd Lencz, and Itsik Pe'er. "The Ashkenazi Jewish Genome." A paper presented at the annual meeting of The American Society of Human Genetics (ASHG) in October 22-26, 2013 in Boston, Massachusetts. The researchers sequenced 128 complete genomes from Ashkenazi Jews. From their results they estimate that about 55 percent plus or minus 2 percentage points of Ashkenazi ancestry derives from European peoples.

Shai Carmi, Ken Y. Hui, Ethan Kochav, Xinmin Liu, James Xue, Fillan Grady, Saurav Guha, Kinnari Upadhyay, Dan Ben-Avraham, Semanti Mukherjee, B. Monica Bowen, Tinu Thomas, Joseph Vijai, Marc Cruts, Guy Froyen, Diether Lambrechts, Stphane Plaisance, Christine Van Broeckhoven, Philip Van Damme, Herwig Van Marck, Nir Barzilai, Ariel Darvasi, Kenneth Offit, Susan Bressman, Laurie J. Ozelius, Inga Peter, Judy H. Cho, Harry Ostrer, Gil Atzmon, Lorraine N. Clark, Todd Lencz, and Itsik Pe'er. "Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins." Nature Communications 5 (September 9, 2014): article number 4835. The complete genomes of 128 Ashkenazi Jewish individuals were examined. Based on their analysis, the authors estimate that Ashkenazi Jews are about 46-50% of European origin, sharing ancestry with Western Europeans like the Flemish, who were also sampled in this study. The authors state that the other contributing population to Ashkenazic genetics are Middle Easterners. Their model suggests the present Ashkenazic population was founded after a bottleneck that occurred 25 to 32 generations ago, that is about "600-800 years" ago. The Ashkenazim have higher heterozygosity than non-Jewish Europeans yet descend from "a recent bottleneck of merely ~350 individuals." Page 63 of their "Supplementary Information" under "Reasons for increased heterozygosity" asserts "Additionally, AJ genomes were shown to have ~3% West-African ancestry." This is highly questionable as the authors cite not their own data to support this claim, but rather the methodologically-flawed study "The history of African gene flow into Southern Europeans, Levantines, and Jews" by Moorjani et al. that appeared in PLoS Genetics 7 in 2011. Most other admixture tests have shown zero or at most 0.1% Sub-Saharan West African/Negroid) ancestry in Ashkenazi individuals, and only tiny amounts of East African as well. Neither the Supplementary Information provided by Carmi et al. nor their main article discuss the evidence for small amounts of East Asian and Slavic ancestry in Eastern Ashkenazi Jews. Excerpt from the Abstract:

Karen Kaplan. "DNA ties Ashkenazi Jews to group of just 330 people from Middle Ages." Los Angeles Times (September 9, 2014). Excerpts:

Jesse Emspak. "Oy Vey! European Jews Are All 30th Cousins, Study Finds." LiveScience (September 9, 2014). Excerpts:

Alkes L. Price, Johannah Butler, Nick Patterson, Cristian Capelli, Vincenzo L. Pascali, Francesca Scarnicci, Andres Ruiz-Linares, Leif Groop, Angelica A. Saetta, Penelope Korkolopoulou, Uri Seligsohn, Alicja Waliszewska, Christine Schirmer, Kristin Ardlie, Alexis Ramos, James Nemesh, Lori Arbeitman, David B. Goldstein, David E. Reich, and Joel N. Hirschhorn. "Discerning the Ancestry of European Americans in Genetic Association Studies." Public Library of Science Genetics (PLoS Genetics) (January 2008). Sampled Southern Italians (Sicilians as well as those on the mainland), and other Europeans - 4,198 individuals in all. Excerpts:

Chao Tian, Roman Kosoy, Rami Nassir, Annette Lee, Pablo Villoslada, Lars Klareskog, Lennart Hammarstrm, Henri-Jean Garchon, Ann E. Pulver, Michael Ransom, Peter K. Gregersen, and Michael F. Seldin. "European Population Genetic Substructure: Further Definition of Ancestry Informative Markers for Distinguishing among Diverse European Ethnic Groups." Molecular Medicine vol. 15(11-12) (November 2009), pages 371-383. Sampled people from Italy (Lombards, Tuscans, Sardinians, Southern Italian-Americans living in New York) and Ashkenazi Jews to genotype them for 300,000 autosomal SNPs. Excerpts:

Chao Tian, Robert M. Plenge, Michael Ransom, Annette Lee, Pablo Villoslada, Carlo Selmi, Lars Klareskog, Ann E. Pulver, Lihong Qi, Peter K. Gregersen, and Michael F. Seldin. "Analysis and Application of European Genetic Substructure Using 300 K SNP Information." Public Library of Science Genetics (PLoS Genetics) (January 2008). Abstract excerpt:

Michael F. Seldin, Russell Shigeta, Pablo Villoslada, Carlo Selmi, Jaakko Tuomilehto, Gabriel Silva, John W. Belmont, Lars Klareskog, and Peter K. Gregersen. "European Population Substructure: Clustering of Northern and Southern Populations." Public Library of Science Genetics (PLoS Genetics) 2(9) (September 2006). Abstract:

Talia Bloch. "One Big, Happy Family: Litvaks and Galitzianers, Lay Down Your Arms; Science Finds Unity in the Jewish Gene Pool." Forward (August 22, 2007). Excerpts:

Anna C. Need, Dalia Kasperaviiute, Elizabeth T. Cirulli, and David B. Goldstein. "A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans." Genome Biology 10(1) (2009): R7 (electronically published on January 22, 2009). Excerpts:

Marc Haber, Dominique Gauguier, Sonia Youhanna, Nick Patterson, Priya Moorjani, Laura R. Botigu, Daniel E. Platt, Elizabeth Matisoo-Smith, David F. Soria-Hernanz, R. Spencer Wells, Jaume Bertranpetit, Chris Tyler-Smith, David Comas, and Pierre A. Zalloua. "Genome-Wide Diversity in the Levant Reveals Recent Structuring by Culture." PLoS Genetics 9(2) (February 28, 2013): e1003316. Participants in this study about the Levant region of West Asia included Sephardi Jews, Ashkenazi Jews, Palestinians, Lebanese Christians, Lebanese Druze, Lebanese Muslims, Syrians, Jordanians, Bedouins, Cypriots, Armenians, Saudis, Yemenis, Iranians, and multiple European, East/South/Central Asian, and African populations. Ashkenazi Jews and Sephardi Jews were found to be closely related to each other and more closely related to Lebanese than Palestinians are. Excerpts:

Doron M. Behar, Ene Metspalu, Toomas Kivisild, Alessandro Achilli, Yarin Hadid, Shay Tzur, Luisa Pereira, Antonio Amorim, Llus Quintana-Murci, Kari Majamaa, Corinna Herrnstadt, Neil Howell, Oleg Balanovsky, Ildus A. Kutuev, Andrey Pshenichnov, David Gurwitz, Batsheva Bonne-Tamir, Antonio Torroni, Richard Villems, and Karl Skorecki. "The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a Recent Founder Event." American Journal of Human Genetics 78 (2006): 487-497. Abstract:

Judy Siegel. "40% Ashkenazim come from matriarchs." Jerusalem Post (January 13, 2006). Excerpts:

Nicholas Wade. "New Light on Origins of Ashkenazi in Europe." The New York Times (January 14, 2006): A12. Excerpts:

Malcolm Ritter. "Study: Most Ashkenazi Jews from four women." Associated Press (January 12, 2006). Excerpts:

Maggie Fox. "Study finds why Jewish mothers are so important." Reuters (January 13, 2006). Excerpts:

Donald Macintyre. "3.5 million Ashkenazi Jews 'traced to four female ancestors'." The Independent (January 14, 2006).

"'Four mothers' for Europe's Jews." BBC News (January 13, 2006). Excerpts:

Hillel Halkin. "Jews and Their DNA." Commentary Magazine 126:2 (September 2008): beginning on page 37. Excerpts:

David B. Goldstein. "In Jewish Genetic History, the Known Unknowns." Forward (August 28, 2009). Excerpts:

Almut Nebel, Dvora Filon, Marina Faerman, Himla Soodyall, and Ariella Oppenheim. "Y chromosome evidence for a founder effect in Ashkenazi Jews." European Journal of Human Genetics 13:3 (March 2005): 388-391. Preceded by advance electronic publication on November 3, 2004. This study focuses on one of the two main non-Mideastern Y-DNA lineages among Ashkenazic Jewish men: haplogroup R1a1 (the other is haplogroup Q). Abstract:

Mait Metspalu, Doron M. Behar, Y. Baran, Saharon Rosset, N. Kopelman, Bayazit Yunusbayev, A. Gladstein, Michael F. Hammer, Shay Tzur, E. Halperin, Karl Skorecki, Richard Villems, and Noah A. Rosenberg. "No indication of Khazar genetic ancestry among Ashkenazi Jews." A paper presented at the annual meeting of The American Society of Human Genetics (ASHG) in October 22-26, 2013 in Boston, Massachusetts. Some of the comparisons here are of questionable utility since the Khazars did not descend originally from the ancient peoples of the Caucasus and there is no proof that modern Caucasus peoples are descended from Khazars. So, the study doesn't directly test for Khazarian descent. Excerpts from the Abstract:

Doron M. Behar, Daniel Garrigan, Matthew E. Kaplan, Zahra Mobasher, Dror Rosengarten, Tatiana M. Karafet, Lluis Quintana-Murci, Harry Ostrer, Karl Skorecki, and Michael F. Hammer. "Contrasting patterns of Y chromosome variation in Ashkenazi Jewish and host non-Jewish European populations." Human Genetics 114:4 (March 2004): 354-365. 442 Ashkenazi Jews were sampled for this study and differentiated according to geographic, religious, and ethno-historical subcategories like "Byelorussian Jews" and "Dutch Jews". In Table 2 on page 357 we see that the mutation lineage designation R-M17, corresponding to haplogroup R1a1 (most often found among Ashkenazi Levites), is found at a frequency of 0.075 among the Ashkenazi Jews as a whole in this study, and at a frequency of 0.264 among the Non-Jewish Europeans (French, Germans, Austrians, Hungarians, Poles, Romanians, and Russians) in the study. Excerpts:

Doron M. Behar, Michael F. Hammer, Daniel Garrigan, Richard Villems, Batsheva Bonne-Tamir, Martin Richards, David Gurwitz, Dror Rosengarten, Matthew Kaplan, Sergio Della Pergola, Lluis Quintana-Murci, and Karl Skorecki. "MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population." European Journal of Human Genetics 12:5 (May 2004): 355-364. (Advance online publication on January 14, 2004.) An observer who read the study indicates that the study shows that approximately 60 percent of European Jewish maternal roots come from European sources, with the other 40 percent from Middle Eastern or Asian roots. Abstract excerpt:

Bayazit Yunusbayev, Mait Metspalu, Mari Jrve, Ildus A. Kutuev, Siiri Rootsi, Ene Metspalu, Doron M. Behar, Krt Varendi, Hovhannes Sahakyan, Rita Khusainova, Levon Yepiskoposyan, Elza K. Khusnutdinova, Peter A. Underhill, Toomas Kivisild, and Richard Villems. "The Caucasus as an asymmetric semipermeable barrier to ancient human migrations." Molecular Biology and Evolution For future print publication. First published online on September 13, 2011. Among many other peoples of the Caucasus, 10 Mountain Jews were sampled to evaluate their haplogroups. These Mountain Jews' Y-DNA haplogroups were as follows: 3 belonged to haplogroup J1e*, 4 to J2a*, 1 to J2a2*, and 2 to L2. These haplogroups suggest overwhelmingly Near Eastern ancestry for the Mountain Jews' paternal lineages (represented by the J haplogroups) and a smaller South Asian element (represented by the L haplogroup).

Dror Rosengarten. "Y Chromosome Haplotypes Among Members of the Caucasus Jewish Communities." Proceedings of the 6th International Conference on Ancient DNA and Associated Biomolecules, July 21-25, 2002. Abstract excerpt:

Stefania Bertoncini, Kazima Bulayeva, Gianmarco Ferri, Luca Pagani, Laura Caciagli, Luca Taglioli, Igor Semyonov, Oleg Bulayev, Giorgio Paoli, and Sergio Tofanelli. "The Dual Origin of Tati-Speakers from Dagestan as Written in the Genealogy of Uniparental Variants." American Journal of Human Biology 24:4 (July/August 2012): pages 391-399. First published online on January 24, 2012. They genetically tested the Y-DNA and mtDNA of two Tat-speaking peoples who live in Daghestan in southern Russia: the Mountain Jews (also called Juhurim) and Muslim Tats. The two communities speak different dialects of the Tat language. The genetics of the Jewish and Muslim Tat speakers were found to be quite different, with the authors saying that they "do not reflect a common ancestry." The Mountain Jews were shown to be "a group with tight matrilineal genetic legacy who separated early from other Jewish communities." In the section "Analysis of paternal lineages", the authors indicate that the dominant Y-DNA haplogroup in Mountain Jews is G-M201 (3M285, P15, and M287), representing 36.8% of their total paternal lineages. The Mountain Jews' branch of G doesn't match the G sublineages of "two major Caucasian linguistic domains" nor does their branch cluster with the G STR Y-DNA haplotypes of Ashkenazim that were reported in Behar et al. 2004 and Hammer et al. 2009. The researchers were surprised that the Mountain Jews' kinds of G "can be separated into at least two divergent clades falling many mutational steps away from any G haplotype ever published before [...] One of these clades is defined by a very peculiar incomplete allele, DYS448*17.4, most likely the results of a deletion external to the repeat units." They also make this observation: "In the MJ [Mountain Jews], the highest level of haplotype sharing (lowest DHS values at the nine-locus level of analysis) was observed with autochthonous groups from Dagestan (Tabasarans, Kubachians, and Laks) and the Jews from Afghanistan". The Y-DNA haplogroup that Mountain Jews share with Tabasarans, called J1*-M267, isn't the same haplogroup that's shared between Muslim Tats and Tabarasans; the two lineages are not even close.

Felice L. Bedford. "Sephardic signature in haplogroup T mitochondrial DNA." European Journal of Human Genetics 20 (2012): 441-448. First released electronically on November 23, 2011. Excerpts from the Abstract:

Christopher L. Campbell, Pier F. Palamara, Maya Dubrovsky, Laura R. Botigu, Marc Fellous, Gil Atzmon, Carole Oddoux, Alexander Pearlman, Li Hao, Brenna M. Henn, Edward Burns, Carlos D. Bustamante, David Comas Martnez, Eitan Friedman, Itsik Pe'er, and Harry Ostrer. "North African Jewish and non-Jewish populations form distinctive, orthogonal clusters." Proceedings of the National Academy of Sciences USA (PNAS). Scheduled for print publication. First published online on August 6, 2012. This investigates the roots of five Jewish populations from North Africa (Moroccan, Algerian, Tunisian, Djerban, and Libyan Jews) and compares them to various Jewish and non-Jewish groups. The researchers found evidence that North African Jews descend from ancient Israelites as well as North African converts to Judaism and confirmed that they intermarried with Sephardic Jews who settled there during the Inquisition era. The degree to which the North African Jewish groups descend from Europeans varied. The study was able to separate Moroccan and Algerian Jews from Djerban and Libyan Jews. The PCA analysis and structure analysis showed that non-Jews of North Africa have more sub-Saharan African ancestry than Jews from North Africa do, confirming earlier studies like Behar et al. 2008.

Dan Even. "International genetic study traces Jewish roots to ancient Middle East." Ha'aretz (August 8, 2012). Excerpts:

A. L. Non, A. Al-Meeri, R. L. Raaum, L. F. Sanchez, and C. J. Mulligan. "Mitochondrial DNA reveals distinct evolutionary histories for Jewish populations in Yemen and Ethiopia." American Journal of Physical Anthropology 144:1 (January 2011): pages 1-10. First published online on July 7, 2010. This study of mtDNA included 45 Yemenite Jewish participants, 41 Ethiopian Jewish paticipants, 50 Yemenite non-Jewish participants, and some Ethiopian non-Jewish participants who speak Semitic language(s). The results showed Yemenite Jews and Ethiopian Jews both have high frequencies of "sub-Saharan African L haplogroups [...] indicating a significant African maternal contribution unlike other Jewish Diaspora populations. However, no identical haplotypes were shared between the Yemenite and Ethiopian Jewish populations, suggesting very little gene flow between the populations and potentially distinct maternal population histories." The authors explain that Ethiopian Jews are maternally Ethiopian rather than Israelite in origin, but they think Yemenite Jews partially have "potential descent from ancient Israeli exiles" and don't believe they have much ethnic Yemenite ancestry.

Noah A. Rosenberg, Eilon Woolf, Jonathan K. Pritchard, Tamar Schaap, Dov Gefel, Isaac Shpirer, Uri Lavi, Batsheva Bonn-Tamir, Jossi Hillel, and Marcus W. Feldman. "Distinctive genetic signatures in the Libyan Jews." Proceedings of the National Academy of Sciences USA (PNAS) 98:3 (January 30, 2001): 858-863. (Mirror) Excerpts:

Yedael Y. Waldman , Arjun Biddanda , Natalie R. Davidson, Paul Billing-Ross, Maya Dubrovsky, Christopher L. Campbell, Carole Oddoux, Eitan Friedman, Gil Atzmon, Eran Halperin, Harry Ostrer, and Alon Keinan. "The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry." PLoS ONE 11:3 (March 24, 2016): e0152056. Autosomal DNA analysis shows that the Bene Israel community of western India was formed by intermarriage between Middle Eastern Jewish men and local Indian women. 18 Bene Israel individuals were compared with hundreds of representatives of Jewish and non-Jewish populations. They have increased lengths of identical-by-descent matches with Jewish populations from outside of India, including Mizrahi Jews, compared to any other population within India or Pakistan. A weakness of this study is that it doesn't compare the Bene Israel against any non-Jewish population from the eastern Middle East (Iran/Iraq area).

Aleza Goldsmith. Jews and Arabs share genes, Stanford research scientist says." Jewish Bulletin of Northern California (March 9, 2001). Excerpts:

Peter A. Underhill, P. Shen, A. A. Lin, L. Jin, G. Passarino, W. H. Yang, E. Kauffman, Batsheva Bonn-Tamir, J. Bertranpetit, P. Francalacci, M. Ibrahim, T. Jenkins, J. R. Kidd, S. Q. Mehdi, M. T. Seielstad, R. S. Wells, A. Piazza, R. W. Davis, M. W. Feldman, Luigi Luca Cavalli-Sforza, and P. J. Oefner. "Y chromosome sequence variation and the history of human populations." Nature Genetics 26 (2000): 358-361. Sequence information for the 167 Y chromosome markers.

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Jewish Genetics, Part 1: Jewish Populations (Ashkenazim ...

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Genetic Testing | Issue List

The Angelina Jolie effect. Health experts have coined the phrase to describe how the actresss public disclosure about her struggle with breast cancer has increased awareness of the benefits of genetic testing as a way to speed treatment for the disease, which kills more than 40,000 American women annually.

In 2013, Jolie had both breasts surgically removed after genetic tests revealed she carries a genetic mutation in her so-called BRCA1 gene that dramatically increases the chance of being diagnosed with potentially fatal breast cancer. The gene defect left the mother of six with an 87 percent greater risk of developing breast cancer and 50 percent risk of ovarian cancer.

Dr. Marisa C. Weiss chief medical officer of the advocacy group Breastcancer.org tells Newsmax Health the actress's decision to go public with details of her double mastectomy and reconstructive surgery was enormously helpful in improving the public's understanding of breast cancer treatment options and the benefits of genetic testing.

Her bravery and willingness to share her story has given a lot of women the courage to step forward and explore their own family history, start a conversation with their doctors about risk, and seek appropriate genetic testing, says Weiss, a breast oncologist in practice at Philadelphias Lankenau Medical Center and the author of five books on the topic.

In an interview with Newsmax Health, Weiss says major advances in genetic research over the past decade now offer women, and men predisposed to developing breast cancer unprecedented opportunities to find out if they are at risk and take appropriate actions that can save their lives.

Excerpts from Wessss interview follow.

Q: What do most women need to know about gene testing?

A: Only 10 percent of breast cancers are mostly due to an inherited genetic mutation, like what Angelina had, BRCA 1. Most women who get breast cancer do not have a family history or an inherited genetic mutation. Most breast cancers occur from the wear and tear of living including a list of modifiable lifestyle, reproductive, and environmental exposures.

All that said, genetic testing is underutilized. Breast cancer is the most common cancer to affect women and even 10 percent of cases adds up to many precious lives. These genetic mutations are associated with a very high level of risk. Finding out if you have an inherited high risk mutation, gives you more options to protect and save your life.

Q: What can you do if you find out you have a genetic mutation?

A: For prevention, finding out about an inherited abnormal breast cancer gene gives you the chance to take steps to prevent cancer before it has the chance to start, with options like risk-reducing medications and prophylactic surgeries.

In addition, there is important family planning, other reproductive choices, and everyday lifestyle choices that can also help. It's also important to take steps to reduce the risk of other cancers which go along with the same genetic mutation, like ovarian cancer. For women diagnosed with breast cancer, finding out if you have an inherited genetic mutation, can have a big impact on selecting your most effective treatment options.

Specific chemotherapies can be extra effective in women with a BRCA1 (and BRCA2) cancer, like Cisplatin. A therapeutic mastectomy might be selected for the treatment of the breast affected by the cancer and a prophylactic mastectomy might be chosen for the other side, to help both reduce the risk of recurrence or the development of a new cancer.

Q: What factors should go into a womans decision about whether to undergo testing?

A: Genetic testing is recommended for women usually 25 or older who are most likely to carry the genetic mutation, like:

Q: What tests are available?

A: Many new tests are available to test for significant inherited mutations. Focused testing on just the three main "founder mutations" on the breast cancer genes, BRCA1 and 2, can be done. Or if a broader range of genes need to be checked out, then "panel testing" may be recommended.

Q: Does a positive test mean a woman will definitely develop breast or ovarian cancer?

A: No. Inherited genetic mutations such as BRCA1 or 2 both convey a high level of life-long risk, ranging from 40-87 percent, depending on the group studied. It's not 100 percent. But given the high risk these genetic mutations produce, it makes sense to find out if you have one, so that you can take the time-sensitive, powerful bold steps required to substantially reduce your high risk.

Q: Is double mastectomy the best solution?

A: Double mastectomy is the single most powerful step to reduce the high risk that is associated with a BRCA 1 or 2 genetic mutation. It can reduce your risk by 90-plus percent. Doing this surgery is not an emergency. But, the sooner this procedure is done, before a cancer has the chance to develop, the greater the chance to avoid getting cancer in the first place.

There are other ways to reduce the risk of breast cancer, like with anti-estrogen hormonal therapy (like tamoxifen), especially in women who carry the BRCA2 mutation that's more likely to be associated with hormone receptor positive breast cancer (BRCA1 mutations are more likely to produce a "triple negative" breast cancer).

Very close surveillance is necessary for women with a BRCA1/2 genetic mutation. For breast surveillance, digital mammography alternating with MRI is recommended every 6 months (e.g. a mammogram in January, MRI in June). An expert clinical breast exam is also important. It is also critical to be followed closely by an ob-gyn expert, to help reduce and watch for the high risk of ovarian, fallopian tubes, and peritoneal cancers (the inside lining of the pelvic and abdominal cavities).

Q: Should men consider a test?

A: Any man with breast cancer should have genetic testing. Women seeking genetic testing who have a family history of breast and related cancers on the father's side may ask their father to obtain genetic testing, to help identify and define the impact of inherited genes in the members of their family.

Most people don't know that genetic risk is equally inherited from your mother and your father.

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Original post:
Genetic Testing: Best Defense Against Breast Cancer?

Genetic testing, any of a group of procedures used to identify gene variations associated with health, disease, and ancestry and to diagnose inherited diseases and disorders. A genetic test is typically issued only after a medical history, a physical examination, and the construction of a family pedigree documenting the genetic diseases present in the past three generations have been considered. The pedigree is especially important, since it aids in determining whether a disease or disorder is inherited and likely to be passed on to subsequent generations. Genetic testing is increasingly being used in genealogy, the study of family origins and history.

A genetic disorder can occur in a child with parents who are not affected by the disorder. This situation arises when a gene mutation occurs in the egg or sperm (germinal mutation) or following conception, when chromosomes from the egg and sperm combine. Mutations can occur spontaneously or be stimulated by environmental factors, such as radiation or carcinogens (cancer-causing agents). Mutations occur with increasing frequency as people age. In men this may result from errors that occur throughout a lifetime as DNA (deoxyribonucleic acid) replicates to produce sperm. In women nondisjunction of chromosomes becomes more common later in life, increasing the risk of aneuploidy (too many or too few chromosomes). Long-term exposure to ambient ionizing radiation may cause genetic mutations in either gender. In addition to these exposure mutations, there also exist two broad classes of genes that are prone to mutations that give rise to cancer. These classes include oncogenes, which promote tumour growth, and tumour-suppressor genes, which suppress tumour growth.

Chemical, radiological, histopathologic, and electrodiagnostic procedures can diagnose basic defects in patients suspected of genetic disease. Genetic tests may involve cytogenetic analyses to investigate chromosomes, molecular assays to investigate genes and DNA, or biochemical assays to investigate enzymes, hormones, or amino acids. Tests such as amino acid chromatography of blood and urine, in which the amino acids present in these fluids are separated on the basis of certain chemical affinities, can be used to identify specific hereditary or acquired gene defects. There also exist numerous genetic tests for blood and blood typing and antibody determination. These tests are used to isolate blood or antibody abnormalities that can be traced to genes involved in the generation of these substances. Various electrodiagnostic procedures such as electromyography are useful for identifying defects in muscle and nerve function, which often result from inherited gene mutations.

Prenatal screening is performed if there is a family history of inherited disease, the mother is at an advanced age, a previous child had a chromosomal abnormality, or there is an ethnic indication of risk. Parents can be tested before or after conception to determine whether they are carriers.

A common prenatal test involves screening for alpha-fetoprotein (AFP) in maternal serum. Elevated levels of AFP are associated with neural tube defects in the fetus, including spina bifida (defective closure of the spine) and anencephaly (absence of brain tissue). When AFP levels are elevated, a more specific diagnosis is attempted, using ultrasound and amniocentesis to analyze the amniotic fluid for the presence of AFP. Fetal cells contained in the amniotic fluid also can be cultured and the karyotype (chromosome morphology) determined to identify chromosomal abnormality. Cells for chromosome analysis also can be obtained by chorionic villus sampling, the direct needle aspiration of cells from the chorionic villus (future placenta).

Women who have had repeated in vitro fertilization failures may undergo preimplantation genetic diagnosis (PGD). PGD is used to detect the presence of embryonic genetic abnormalities that have a high likelihood of causing implantation failure or miscarriage. In PGD a single cell is extracted from the embryo and is analyzed by fluorescence in situ hybridization (FISH), a technique used to identify structural abnormalities in chromosomes that standard tests such as karyotyping cannot detect. In some cases DNA is isolated from the cell and analyzed by polymerase chain reaction (PCR) for the detection of gene mutations that can give rise to certain disorders such as Tay-Sachs disease. Another technique, known as comparative genomic hybridization (CGH), may be used alongside PGD to identify chromosomal abnormalities.

Advances in DNA sequencing technologies have enabled scientists to reconstruct the human fetal genome from genetic material found in maternal blood and paternal saliva. This in turn has raised the possibility for development of prenatal diagnostic tests that are noninvasive to the fetus but capable of accurately detecting genetic defects in fetal DNA. Such tests are desirable because they would significantly reduce the risk of miscarriage that is associated with procedures requiring cell sampling from the fetus or chorionic villus.

Chromosomal karyotyping, in which chromosomes are arranged according to a standard classification scheme, is one of the most commonly used genetic tests. To obtain a persons karyotype, laboratory technicians grow human cells in tissue culture media. After being stained and sorted, the chromosomes are counted and displayed. The cells are obtained from the blood, skin, or bone marrow or by amniocentesis or chorionic villus sampling, as noted above. The standard karyotype has approximately 400 visible bands, and each band contains up to several hundred genes.

When a chromosomal aberration is identified, it allows for a more accurate prediction of the risk of its recurrence in future offspring. Karyotyping can be used not only to diagnose aneuploidy, which is responsible for Down syndrome, Turner syndrome, and Klinefelter syndrome, but also to identify the chromosomal aberrations associated with solid tumours such as nephroblastoma, meningioma, neuroblastoma, retinoblastoma, renal-cell carcinoma, small-cell lung cancer, and certain leukemias and lymphomas.

Karyotyping requires a great deal of time and effort and may not always provide conclusive information. It is most useful in identifying very large defects involving hundreds or even thousands of genes.

Techniques such as FISH, CGH, and PCR have high rates of sensitivity and specificity. These procedures provide results more quickly than traditional karyotyping because no cell culture is required. FISH can detect genetic deletions involving one to five genes. It is also useful in detecting moderate-sized deletions, such as those causing Prader-Willi syndrome. CGH is more sensitive than FISH and is capable of detecting a variety of small chromosomal rearrangements, deletions, and duplications. The analysis of individual genes also has been greatly enhanced by the development of PCR and recombinant DNA technology. In recombinant DNA technology, small DNA fragments are isolated and copied, thereby producing unlimited amounts of cloned material. Once cloned, the various genes and gene products can be used to study gene function both in healthy individuals and those with disease. Recombinant DNA and PCR methods can detect any change in DNA, down to a one-base-pair change, such as a point mutation or a single nucleotide polymorphism, out of the three billion base pairs in the human genome. The detection of these changes is facilitated by DNA probes that are labeled with radioactive isotopes or fluorescent dyes. Such methods can be used to identify persons who are carriers for inherited conditions, such as hemophilia A, polycystic kidney disease, sickle cell anemia, Huntington disease, cystic fibrosis, and hemochromatosis.

Biochemical tests primarily detect enzymatic defects such as phenylketonuria, porphyria, and glycogen-storage disease. Although testing of newborns for all these abnormalities is possible, it is not cost-effective, because some of these conditions are quite rare. Screening requirements for these disorders vary and depend on whether the disease is sufficiently common, has severe consequences, and can be treated or prevented if diagnosed early and whether the test can be applied to the entire population at risk.

Once the domain of oral traditions and written pedigrees, genealogy in the modern era has become grounded in the science of genetics. Increased rigour in the field has been made possible by the development and ongoing refinement of methods to accurately trace genes and genetic variations through generations. Genetic tests used in genealogy are mainly intended to identify similarities and differences in DNA between living humans and their ancestors. In some instances, however, in the process of tracing genetic lineages, gene variations associated with disease may be detected.

Methods used in genealogical genetics analysis include Y chromosome testing, mitochondrial DNA (mtDNA) testing, and detection of ancestry-associated genetic variants that occur as single nucleotide polymorphisms (SNPs) in the human genome. Y chromosome testing is based on genetic comparison of Y chromosomes, from males. Because males with a common male ancestor have matching Y chromosomes, scientists are able to trace paternal lineages and thereby determine distant relationships between males. Such analyses allow genealogists to confirm whether males with the same surname are related. Likewise, maternal lineages can be traced genetically through mtDNA testing, since the mitochondrial genome is inherited only from the mother. Maternal lineage tests typically involve analysis of a segment in mtDNA known as hypervariable region 1; comparison of this segment against reference mtDNA sequences (e.g., Cambridge Reference Sequence) enables scientists to reconstruct an individuals maternal genetic lineage.

Following the completion of the Human Genome Project in 2003, it became possible to more efficiently scan the human genome for SNPs and to compare SNPs occurring in the genomes of human populations in different geographical regions of the world. The analysis of this information for genetic testing and genealogical purposes forms the basis of biogeographical ancestry testing. These tests typically make use of panels of ancestry informative markers (AIMs), which are SNPs specific to human populations and their geographical areas that can be used to infer ancestry. In 2010 a study using genome-wide SNP analysis incorporating ancestral information successfully traced persons in Europe to the villages in which their grandparents lived. The technique was expected to advance genetic testing intended to map an individuals geographical ancestry.

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genetic testing | Britannica.com