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When Genetic Screening Goes Very, Very Wrong

Based on genetic testing, 20 members of the same family were misdiagnosed with a potentially fatal heart condition.
October 31, 2016, 2:30pm
Image: pedrosala/Shutterstock

Teenagers don't routinely drop dead of cardiac failure. As a cause of death among individuals aged 12 to 19, heart disease barely even rates, staking out a mere 3 percent of all fatalities. It makes sense: heart problems are so often accumulative, the result of a lifelong progression toward disease. Accidents, meanwhile, just happen.

So, when a 13-year-old boy died suddenly of cardiac arrest, it signaled a greater concern. Heart disease at a young age is more often than not the result of a built-in abnormality—a fate predicted by faulty genes. It's reasonable then for such a death to cause concern among those that might happen to share the same genes. With this in mind, a large number of the boy's relatives underwent genetic testing. Twenty of them were subsequently diagnosed with long QT syndrome, an inherited heart rhythm condition characterized by bouts of fast, chaotic heartbeats. It can lead to seizures and even sudden death. It's the sort of thing you'd really want to know about.

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According to a kind of disturbing paper published this week in the Mayo Clinic Proceedings, these diagnoses were mistakes. In fact, in seeking a second opinion at the Mayo Clinic, none of the family members that had initially received the diagnosis showed any signs of the disease in treadmill stress testing. None of them had ever even shown symptoms of long QT syndrome. They left cleared of the disease.

But, still, better safe than sorry, right? Not exactly. As a result of the initial long QT diagnosis, the brother of the boy who died had a cardioverter defibrillator implanted in his chest. It works by detecting heart arrhythmias and delivering shocks to the heart to get things back on track. On at least two occasions, it had delivered mistaken shocks. It sounds like a uniquely unpleasant experience.

In a statement, Michael Ackerman, the lead author of the new paper, argues that this is a case of putting genotype above phenotype, which is (or should be) a general concern with genetic testing. Genetic diseases occur when genetic abnormalities are expressed under the right set of environmental and/or biological conditions, resulting in a set of characteristics known as a phenotype. The genotype, meanwhile, consists of the actual genetic code. This is a general problem with personalized medicine and the genetic testing explosion—conflating disease with genes—and long QT syndrome happens to be a classic case.

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In a 2011 review, Dan Roden, a experimental therapeutics researcher at Vanderbilt University, termed this the genotype–phenotype dilemma. "We are in the increasingly awkward position of identifying individuals who carry genetic variants that, in some patients (perhaps their own family members), may confer susceptibility to a severe disease and yet in the affected individual have no clinical phenotypes," he wrote.

"With the increasing availability of genetic information will come an explosion in needless diagnostic testing and therapeutic interventions."

As it turns out, a likely majority of those with genetic mutations linked to long QT syndrome will never have symptoms. What makes this such a poignant dilemma is that still some people will have symptoms. And some of them will be relatively young people dying of sudden cardiac failure. The impulse to intervene then starts to seem reasonable, even in the absence of a clear disease phenotype. Yet, to put a statistic to it, Ackerman estimates that about 40 percent of patients that show up at the Mayo Clinic with a long QT syndrome diagnosis leave without it.

"Developing mechanisms to understand which genetic variants do not require intervention and which might carry clinical implications represents the major challenge to modern genetics and indeed to contemporary medical practice over the next several decades," Roden wrote. "This problem must be solved. Otherwise, with the increasing availability of genetic information will come an explosion in needless diagnostic testing and therapeutic interventions."

The teenager at the center of the current case study was presumed to have died of cardiac failure related to long QT syndrome, but the nullification of the 20 diagnoses led Ackerman and co. to investigate further. To this end, they performed a technique known as a "molecular autopsy," a forensic medicine technique often used in cases of sudden cardiac death where traditional autopsy methods may not suffice.

"We discovered that the boy died tragically from an abnormal heart muscle condition caused by an entirely different genetic defect—unrelated to long QT syndrome—that was confined to only the sudden death victim," Ackerman says.

The case is ultimately kind of a dystopia in miniature, one that resulted in a lot of unnecessary fear and and at least some physical pain. Genetic screening seems like such a great answer to disease, but genetic diseases need more than genes. Thinking otherwise can have dangerous consequences.