The Molecular Autopsy in Evaluating Sudden Death

Michael J Ackerman, MD, PhD; Frank Cetta Jr, MD


February 29, 2016

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Sudden Death in the Young

Frank Cetta Jr, MD: Hello, I'm Frank Cetta, professor of pediatrics and medicine at Mayo Clinic. During today's recording, we'll be discussing the molecular autopsy.

I'm joined today by my colleague, Dr Michael Ackerman, professor of medicine, director of the Genetic Heart Rhythm Clinic and the Sudden Death Genomics Laboratory here at Mayo Clinic, Rochester.

Mike, during the fall/autumn high school and collegiate sports seasons, you can't pick up a newspaper in any major city in the United States without seeing there was a sudden death on a football field, a basketball court, or a soccer field. I think that serves as the basis and the importance of what we're going to discuss today.

Where are we with the current state of evaluating sudden death in young athletes?

Michael J. Ackerman, MD, PhD: Frank, it's great to be here with you. Any time there's one of these youthful sudden deaths, it's absolutely tragic. It's small in number, thank goodness, but whenever one of these happens, it grips the nation, it grips the community, and it tears apart that family.

Evaluating the Sudden Death Victim

Dr Ackerman: We currently have on the order of one to 5000 youthful sudden deaths in the United States each year, athletes and nonathletes alike. Unfortunately, we have nonuniformity, at best, and perhaps a broken system, at worst, when it comes to evaluating that sudden-death victim. It really depends on: Where did it occur? Is it a medical-examiner jurisdiction? Is it a county-coroner jurisdiction? Did an autopsy even happen? How thorough was the vetting of the autopsy? So we don't really even truly know the epidemiology of sudden death.

The [National Institutes of Health] NIH and [Centers for Disease Control and Prevention] CDC have recognized this, and they just recently launched a Sudden Death in the Young (SDY) Registry to try to get a handle on the epidemiology and etiology of sudden death so that we do a more uniform job in the postmortem evaluation of the sudden-death victim and in that sudden-death victim's living family members. With the survivors, we do a really haphazard job when the siblings come or the family members of a decedent come. It ranges from just condolences—"this is awful"—to ordering every genetic test, every test, every cardiac test on those relatives and, perhaps, ordering it every year.

The Role of the Molecular Autopsy

Dr Cetta: You have been involved with sudden death issues your entire career. This summer, in Circulation[1], you were part of a group that had access to the [National Collegiate Athletic Association] NCAA database, and you looked at over a decade, from 2003 to 2013, the sudden deaths that occurred in the NCAA. You guys highlighted a few high-risk groups—males, black athletes, I think basketball players were also listed in there. It's interesting in that paper that the structural autopsy frequently was negative.

How does the molecular autopsy play into this? Maybe you could help us with that: what is a molecular autopsy, and how often is it positive/negative, and how does it help us?

Dr Ackerman: The molecular autopsy—another word for it or expression is postmortem genetic testing. It's really doing a genetic interrogation to ask the question: Could that sudden death have stemmed from a single genetic cause? A lot of times, people think of the molecular autopsy only when the conventional autopsy is completely negative—an autopsy-negative sudden unexplained death. In that study, among those collegiate athletes who died, half of all of the deaths had no explanation by eye or by microscope. So the molecular autopsy is thought to play a role there when the cause of death was a channelopathy, an electrical disorder that would leave no clues during a conventional autopsy. But it may be that a molecular autopsy actually works the best and is the most powerful and informative when the medical examiner or the coroner or the forensic scientist says, I know it was hypertrophic cardiomyopathy (HCM). Then when we do the genetic tests looking at known HCM genes and get concordance, we have not only provided definitive closure as to cause, but now we have a diagnostic gold-standard biomarker for the rest of the family.

So the yield—how often is it positive? It depends on what was the root cause. If the root cause was clearly hypertrophic cardiomyopathy, that molecular autopsy probably will be 80% positive. If the root cause was "we have no idea why, the autopsy is completely clean, stone-cold normal," then the likelihood of a positive genetic test in that decedent ranged, in our work, from about 10% to 40%, and then it depended on the narrative.

Not all sudden death is the same. Sudden death in bed of a 30-year-old is very different than an autopsy-normal sudden death of a 5-year-old while playing on the playground. Exertional triggers give us a higher yield of finding a potential genetic explanation.

The Challenges of Getting a Molecular Autopsy

Dr Cetta: Maybe you could address the challenges of this, both for us as practitioners and for the families as well. How do we obtain one of these, especially after someone has died? We know how to see a patient in clinic, a live patient in clinic, order a test, a blood sample gets sent to a lab. or it gets processed and sent somewhere to a lab.

How do we go about this after we have an unexplained death?

Dr Ackerman: Here we have several challenges. I think we have three. First of all, we the clinicians, need to go back to our communities, wherever we are, and check with the medical examiners, the county coroner's offices and see what their standard operating procedures are. In other words, do they procure tissue in a way that would be DNA-friendly, that would lend itself to doing postmortem genetic testing? Unfortunately, the answer is often no, all we have is a paraffin-embedded block of tissue. So we really need to get a change to where, uniformly, when there's a sudden death, blood and EDTA will always be obtained. Blood will be put on a blood spot card or a piece of tissue would be frozen so that we could potentially ask a genetic question.

Now let's say we achieve that and we now have the available DNA-friendly tissue, the second challenge is reimbursement. If the third-party mix and the reimbursement landscape is one where they don't like to pay for things when we're alive, they really don't like to pay for genetic testing when we're dead. That forces us to do potentially everything on the surviving relatives, when maybe the most cost-effective thing to do would be to start with the decedent where he or she holds the answer. They've died for some reason, and maybe a genetic autopsy or a molecular autopsy would get us there.

The third challenge, unfortunately, is now that programs are starting to do molecular autopsies, they are challenged with decoding the information. In other words, they're finding a genetic variant in their 20,000 genes, and they're quick to pronounce "guilty" and rush to a judgment with that variant as the cause. I've often said that the only thing worse than telling a family "We have no idea why Johnny or Sally died" is to tell them that we have found the genetic answer and we're wrong.

Those are three of the challenges that face us right now with doing a molecular autopsy.

Dr Cetta: Thanks very much, Mike. These were great insights. This is an important issue in our country. Those of us who take care of young people and their families grapple with this on a daily basis, and I think we learned a lot from this.

Thanks to you for joining us today and tuning into Mayo Clinic discussion at on Medscape.


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