by Jeanne Erdmann
Nature, November 7, 2013
Genetic testing of the dead for inherited heart rhythm disorders could help resolve about one fourth of sudden death autopsies that would otherwise remain unexplained – and potentially save lives of surviving family members – if only the test were used more often. But how and whether to implement such tests relates to a broader question rampant in the burgeoning field of genetic testing: When someone tests positive for a genetic disease that can be prevented with an expensive and sometimes risky procedure (whether it’s BRCA, or inherited cardiac problems), how much treatment does a person without symptoms need?
In June, 2001, twelve-year-old Ben Frost grabbed his hockey stick, and stepped onto the ice in Auckland City, New Zealand. Frost collapsed five minutes into the game, his heart sent into a chaotic rhythm. Frost had collapsed three times before, once nearly drowning when he sunk to the bottom of a pool. This time though, he never recovered, even with immediate CPR from a nearby nurse, or from a defibrillator administered ten minutes later by EMTs.
For a while, Frost’s death, like thousands of other sudden deaths each year, went unexplained, even after autopsy. Eventually, his case came to the attention of Jon Skinner, a pediatric cardiologist at Auckland’s Starship Hospital. Skinner had already seen too many young patients who had lost a parent, or a sibling like Frost, only to have the autopsy come back negative. Skinner suspected that many of these deaths were caused by inherited cardiac arrhythmias that kill like silent assassins, leaving two tragedies in their wake: family members grieving a loss without explanation, and without the knowledge that they too could face a similar death. Skinner used Ben Frost’s case to spur a nationwide program in New Zealand in which every sudden unexplained death in people ages one to 40 are referred for post-mortem genetic
testing. A government agency picks up the tab, which ranges from $3000 to $5000 dollars.
Skinner is one of a handful of cardiologists who are pushing for post-mortem genetic testing in such cases. Their efforts would be impossible without the work of Michael Ackerman, a pediatric cardiologist and researcher at Mayo Clinic in Rochester, Minnesota, and the leading researcher in the world on molecular autopsies. Even though Ackerman heads Mayo’s Sudden Death Genomics Laboratory, and even though he discovered many of the mutations used in commercial genetic tests for heart rhythm disorders, he can’t turn to molecular autopsies as often as he’d like, because in the US, there’s no third-party reimbursement. Ackerman relies on public and private funding and philanthropic donations to pay the cost of post-mortem genetic testing, which only covers the rare cases in his research protocols. Everyone else pays out of pocket.
I’m proposing a feature on post-mortem genetic testing. I’d write the story highlighting Ackerman’s efforts to secure genetic tests in cases of sudden unexplained death. For the narrative framework, I’ll find a family that Ackerman worked with on such testing, and follow their experience through the story. This story is timely, because in the US, nearly every day, I read news accounts of young athletes dying of sudden cardiac arrest, (and these are the only cases that make the news), yet post-mortem genetic testing is rarely done here, even though Skinner has proven that it’s a good way to screen community health, and physicians with Ackerman’s star power are strong proponents.
A feature on molecular autopsies would provide a compelling way to talk about the scientific and societal challenges of genetic testing, especially the all-important question about what to do with the answer one gets – because these challenges are not are not isolated to sudden cardiac deaths. As recent news coverage of Angelina Jolie’s choice of preventive surgery shows, once a genetic test comes back positive for an inherited risk of a deadly problem, the course of action itself can be risky, expensive, and not always clear cut. Doctors may want to treat any surviving first-degree family member (parents and siblings) who test positive for a deadly genetic mutation as if they already have the disease. Even if they do not have symptoms; most often they don’t.
I’ve chosen cardiology to tell this story because the stakes are so high. “In our business we can’t be wrong, and that’s the hard part about this,” Dr. Phillip Cuchulich, a cardiologist and electrophysiologist, says.
Critics say that we don’t have a grasp of what genetic test results mean. Quite often, for example, cardiac genetic tests are not clearly positive or negative; test results come back with variations that doctors haven’t seen before, so it’s difficult to sort through whether such mutations are harmless, or whether results raise the risk of disease, which in turn raises anxiety levels in surviving family members.
Finally, much has been published showing the benefits of molecular autopsies. The field has spurred new studies in stem cells: Some cardiologists are taking skin samples and reprogramming them (using methods for induced pluripotent stem cells), into patient- specific cardiac muscle cells. Such research may help answer why some patients carry harmful mutations but do not have symptoms – and may never succumb to the disease.
Perhaps this will help doctors choose which asymptomatic persons to treat and which persons can be safely left alone.
As this story falls within the guidelines of my fellowship from the Commonwealth Foundation, which covers health performance, I can use part of my travel budget to visit with Ackerman at Mayo.
I look forward to your response.