What Rare Disorder Is Hiding in Your DNA?

Posted: December 31, 2014 at 4:51 am

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As comprehensive genetic tests become more widespread, patients and experts mull how to deal with unexpected findings

Skip Sterling

Last spring Laura Murphy, then 28 years old, went to a doctor to find out if a harmless flap of skin she had always had on the back of her neck was caused by a genetic mutation. Once upon a time, maybe five years ago, physicians would have focused on just that one question. But today doctors tend to run tests that pick up mutations underlying a range of hereditary conditions. Murphy learned not only that a genetic defect was indeed responsible for the flap but also that she had another inherited genetic mutation.

This one predisposed her to long QT syndrome, a condition that dramatically increases the risk of sudden cardiac death. In people with the syndrome, anything that startles themsay, a scary movie or an alarm clock waking them from a deep slumbermight kill by causing the heart to beat completely erratically.

Doctors call this second, unexpected result an incidental finding because it emerged during a test primarily meant to look for something else. The finding was not accidental, because the laboratory was scouring certain genes for abnormalities, but it was unexpected.

Murphy, whose name was changed for this story, will most likely have plenty of company very soon. The growing use of comprehensive genetic tests in clinics and hospitals practically guarantees an increasing number of incidental discoveries in coming years. Meanwhile the technical ability to find these mutations has rapidly outpaced scientists understanding of how doctors and patients should respond to the surprise results.

Unknown Unknowns Incidental findings from various medical tests have long bedeviled physicians and their patients. They appear in about a third of all CT scans, for example. A scan of the heart might reveal odd shadows in nearby lung tissue. Further investigation of the unexpected resultseither through exploratory surgery or yet more testscarries its own risks, not to mention triggering intense anxiety in the patient. Follow-up exams many times reveal that the shadow reflects nothing at alljust normal variation with no health consequences.

What makes incidental findings from genetic tests different, however, is their even greater level of uncertainty. Geneticists still do not know enough about how most mutations in the human genome affect the body to reliably recommend any treatments or other actions based simply on their existence. Furthermore, even if the potential effects are known, the mutation may require some input from the environment before it will cause its bad effects. Thus, the presence of the gene does not necessarily mean that it will do damage. Genetics is not destiny. In Murphy's case, her mutation means that she has a roughly 50 to 80 percent chance of developing long QT syndrome, and the presence of the mutation alone is not a sure indicator she will be afflicted, says her physician, Jim Evans, a genetics and medicine professor at the University of North Carolina School of Medicine. To be safe, he has advised her to meet with a cardiac specialist to talk about next steps, including possibly starting beta-blocker drugs to regularize her heart rate.

The incidence of hard-to-interpret results is expected to rise because the cost of surveying large swaths of the genome has dropped so lowto around $1,000. It is typically less expensive to get preselected information about the 20,000 or so genes that make up a person's exomethe section of the genome that provides instructions for making proteinsthan to perform a more precision-oriented test that targets a single gene. As a consequence, scientists and policy makers are now scrambling to set up guidelines for how much information from such testing to share with patients and for how best to help them deal with the inevitable incidental findings.

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What Rare Disorder Is Hiding in Your DNA?

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