American College of Physicians: Internal Medicine — Doctors for Adults ®

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Internists becoming the ‘gatekeepers’ for genetic testing

From the June ACP Internist, copyright 2012 by the American College of Physicians

By Jennifer Kearney-Strouse

Genetics may be the “topic less traveled,” but it's no longer something internists can ignore, according to Matthew Taylor, MD, PhD.

The field of genetic testing has advanced very quickly in the past two decades, and internists play an important role in determining how such testing should be used, said Dr. Taylor, an internist and geneticist who is the director of adult clinical genetics at the University of Colorado Denver. He spoke on “Common Genetics Issues in General Internal Medicine: Integrating Genetic Testing into Clinical Practice” at Internal Medicine 2012 in April.

Dr. Taylor

Dr. Taylor



Internists need to know how to determine whether a disease might be genetic, whether a genetic test for the disease is available, and how the results should be interpreted. Internists are also called on for diagnosis, prognosis, family risk assessment and treatment of genetic diseases.

Genetic testing remains complicated and the interpretation of test results is not always straightforward. “This is not a pregnancy test kind of situation, where the results are quite binary,” Dr. Taylor noted. “As the internist, you're the gatekeeper here.”

And although internists as a group may not always feel comfortable with genetics, a majority of their patients probably expect them to be, Dr. Taylor said. A survey by the American Medical Association in March 1998 found that 59% of Americans were somewhat or very likely to take advantage of genetic testing and that 72% believed that their primary care physician would be able to interpret the results. Dr. Taylor said those numbers have most likely gone up rather than down in the 14 years since the survey was done.

What to look for

When clinicians are trying to determine whether a disease or condition is related to a genetic disorder, there are some clues to look for, Dr. Taylor said. The most obvious category is known genetic disorders that present with a certain physical characteristic or phenotype, such as achondroplasia.

These disorders are of growing relevance to internists, Dr. Taylor said, because with advances in pediatric care, patients who previously would not have survived to adulthood are living long enough to develop conditions like high cholesterol, hypertension, and adult-onset diabetes. “You're going to see these patients in your practice,” Dr. Taylor said.

Internists should also be alert for any family history of a genetic disorder, which patients often bring up themselves. “Maybe the patient comes in and says something like ‘I'm really worried about what's happened to five or six of my relatives,’” Dr. Taylor said.

Premature presentation of a disease can be another red flag. If the usual risk factors aren't present or haven't been there long enough to cause disease, the early presentation could be genetic, Dr. Taylor said.

Unusual presentations, such as breast cancer in a man, or unexpected natural progression can also indicate genetic causes. “Those unusual cases that just don't make sense, some of those are driven by genetics,” Dr. Taylor said.

Deciding to test

If a genetic test for the potential disorder is available, an internist should consider whether testing is needed. Good reasons for testing include to confirm a diagnosis or to determine prognosis. For example, genetic testing can pinpoint whether a patient with the gene for Huntington's disease will have a mild, moderate or severe form.

“A 30-year-old man with Huntington's disease, untreatable, going to die from it: Are the symptoms likely to occur in the next three to five years, or the next 10 to 15 years? If you were that individual, you might live your life quite differently having that information,” Dr. Taylor said.

Genetic testing can be important for performing a family risk assessment, which is “something that we as internists aren't very good at doing,” Dr. Taylor said, but can be a very powerful motivator for patients to undergo testing.

“[They] want to know if the disease they have has a bearing on their children, both the children they have as well as the children they're planning on having,” he said.

Test results can also help in determining patients' treatment. Treatment and management based on genetic testing can include prophylactic surgery for hereditary cancer; avoidance of volatile anesthetics for malignant hyperthermia; personalized medication regimens for drugs like warfarin and clopidogrel, whose efficacy can vary by genetic makeup; and expectant screening for hereditary syndromes of cancer, cardiomyopathies, endocrinopathies, and renal disease, among others, he said.

However, there are also downsides to genetic testing, such as cost, specificity issues and questionable predictive value. Physicians and patients may also be concerned that genetic test results may up the odds for future discrimination, although the Genetic Information Nondiscrimination Act, or GINA, which was signed into federal law by George W. Bush in 2008, restricts the ways health insurers and employers can use such information.

“My message is not to say that ‘Testing is here, we should just use it,’” Dr. Taylor stressed. “There are lots of technologies that come into medicine that have pluses and minuses associated with them. We shouldn't just blindly use those technologies because they're available and because someone has a nice brochure about how well their test works.”

Interpreting results

There are four basic possible results of a genetic test, Dr. Taylor said. When a result is positive, it means that the test detected a genetic mutation that is probably causing disease. This result can be used to evaluate both the patient and potential risk in other relatives, Dr. Taylor said. If relatives test positive on the same test, they are at risk; if they test negative, they are not at risk.

When a test result is negative, or no pathogenic mutation is detected, it can mean that the patient does not have the disease or that the result is a false negative, as the sensitivity of many genetic tests is incomplete.

“Be careful. You cannot use that ‘negative’ test to evaluate the risk in other relatives,” Dr. Taylor said. “If you don't know what the genetic cause of the disease is in your particular family you're looking at, you can't go and test the at-risk relatives to figure out whether they're at risk because you don't know what you're looking for. You have to find that mutation first.”

Genetic tests can also detect polymorphism, or common variants in a gene. “There's lots of genetic variation out there. Genetic tests will sometimes find a genetic change which has not been reported or studied before. It may not actually be causing disease,” Dr. Taylor said.

Variants of uncertain significance, or VUS, are another potential result. These are variants that are located in the gene of interest but have an unknown effect on the development of disease.

“The important thing is not to treat this as a positive test result,” Dr. Taylor stressed. “The majority of these VUS are proven to probably not be associated with disease. When you're doing a genetic test, it's the positive test that's the most important.”

To demonstrate how genetic testing can help change clinical practice, Dr. Taylor referred to a study published in 2001 in the New England Journal of Medicine that examined two families with a strong history of gastric cancer.

Before genetic testing was available, two family members opted for prophylactic gastrectomy based on their family history. They had both undergone routine surveillance with imaging and endoscopic biopsies and had had negative results but opted for the surgery anyway. At surgery, one of the women was found to already have diffuse gastric cancer that biopsies had missed, while the other was cancer-free.

Eventually, the genetic mutation responsible for the gastric cancer was discovered, and with testing available, four family members who tested positive decided to have prophylactic gastrectomies. Again, all had been undergoing routine surveillance every six months with imaging and endoscopic biopsies with negative results, but at surgery, all four had gastric cancer that surveillance had missed.

Before genetic testing was an option, Dr. Taylor said, the decision to have a gastrectomy had to be based solely on family history, leading to life-saving surgery in one woman and unnecessary surgery in another.

“On the other hand, you had one, two, three, four individuals who were able to wait until testing was available. They had surgery. They at least will not die of stomach cancer,” he said. “You used the genetic test to really change the management of these four individuals.”

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Online resources

Matthew Taylor, MD, PhD, director of adult clinical genetics at the University of Colorado Denver, recommends the following online genetics resources for clinicians.

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