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When A Traditional Autopsy Fails, DNA May Have the Answer

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When A Traditional Autopsy Fails, DNA May Have the Answer

Jul 27, 2016

The unexpected death of a child is tragic under any circumstance, but it becomes even more so when the reason why is unknown. Martin Tristani-Firouzi, MD, a pediatric cardiologist at the University of Utah, leads the Sudden Death in the Young Center which is searching the DNA of the deceased for an explanation of why they died unexpectedly. He explains what they are searching for and how results from a genetic autopsy could also save other members of the family.

Episode Transcript

Interviewer: Searching DNA for clues to the cause of death, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs. "The Science and Research Show" is on The Scope.

Interviewer: I'm talking with Dr. Marty Tristani-Firouzi, a pediatric cardiologist at the University of Utah. Paint me the scene here, a child dies unexpectedly, which is a horrible situation in any case. But, if it's not clear why the child died, what's typically done to find the cause of death?

Dr. Firouzi: There is an investigation at the scene to try and understand the circumstances of the death. A lot of infants that die, and fall into the category of sudden infant death syndrome may have certain situations with sleeping on a mattress which isn't firm, or somehow they became smothered, someone rolled on top of them. That sort of a thing would identify a cause of death. But more commonly, an autopsy is required. And the autopsy then rules out unknown cancers. It can also reveal trauma that would be a non-accidental death. Frequently, the autopsy ends up being negative. And then we get back to the situation where the family is told, "We really don't know why your child died."

Interviewer: There must be a presumption that the heart is the cause for the many of these sudden deaths. Is that true?

Dr. Firouzi: That is true. And I think the literature supports that as a general assumption. It's such a profound event. The heart is so crucial in maintaining our survival. And we know that arrhythmias can cause sudden death. In patients that are known to have specific diseases, some of them will suffer a sudden cardiac death. And so by excluding the pathology, by saying these are autopsy-negative sudden deaths, in the young, I think the majority of clinicians in the country would presume they were arrhythmic until proven otherwise

Interviewer: Part of what you're doing, is kind of getting beyond the traditional autopsy. Why is it not enough?

Dr. Firouzi: If the heart looks normal structurally, even under histology, the heart can look completely normal and yet these individuals can have died of an arrhythmic death and have other family members. And so . . .

Interviewer: So a heart arrhythmia . . .

Dr. Firouzi: A heart arrhythmia where the heart beats too fast or too slow and that results in sudden death. So the term "molecular autopsy" refers to the ability to do DNA analysis of the deceased victim and that really goes the step beyond the traditional histological autopsy.

Interviewer: What can the DNA tell you?

Dr. Firouzi: The hope is to perform genetic analysis of the deceased individual and identify either known variants and known genes that cause inherited arrhythmias or novel genes that we haven't yet associated with arrhythmic risks. And our hope is that we can find this in deceased individual and then sequence the first-degree relatives and find out whether other family members carry that damaging variant.

Interviewer: Why is it important to know the cause of death? I mean, it's something that's already happened so it just for peace of mind or are there other reasons as well?

Dr. Firouzi: Sure, that's a great question. A lot of families want to know why so that they can have some sense of closure. But I think more importantly is whether other family members are at risk. So for the arrhythmic types of death, many times these arrhythmias run in the family and the family may not know that. And this sort of sentinel finding of sudden can occur in these types of inherited arrhythmias. And the question then is who else in that family is at risk of dying suddenly? And this is a very difficult thing for families to process because they're in this grieving process and then finally they're told that maybe they have something in their family and maybe their other children will have the same demise.

Interviewer: So even if this one child dies at a very young age, there could be older members of the family that are still at risk?

Dr. Firouzi: Absolutely. That is exactly right.

Interviewer: So what exactly are you looking for in the DNA?

Dr. Firouzi: There are specific families of arrhythmias. The most common and probably the most well recognized is the family of long Q-T syndrome, of which there are up to twelve genes that have been implicated in long Q-T syndrome. What we see, at least in Long Q-T syndrome and a lot of other inherited arrhythmias, there are other family members that carry that disease variant. And they may be normal. They may have normal electrocardiograms if we put them under stress, like an exercise stress test. Sometimes they will behave normally as well.

But if we further stress them by giving them a medication and testing whether they have electrocardiographic findings, sometimes under those more extreme circumstances, we can uncover the clinical phenotype that is consistent with the disease. And so the key part of this is not just to do the DNA analysis on the deceased, but to do a clinical analysis and a DNA analysis on the first-degree relatives.

Interviewer: And you had mentioned too that a part of this whole initiative is discovery as well. I mean, there are some genetic variants that we know about, but there are probably a lot we don't know about.

Dr. Firouzi: Yes, absolutely. So there have been a few studies that have used this concept of the molecular autopsy where they go through sequentially and look at a series of individuals that had died suddenly. And in maybe 20% of those sudden death victims, you can find a variant in a known gene that is known to cause arrhythmia disorders and sudden death.

But the majority don't have a simple variant. And the fact that they died from an arrhythmic death, presumably, would suggest that indeed they have some genetic disorder and that variant may lie outside the coding region, which outside the exome in the whole genome space in some area that has not been well characterized. And the majority of DNA has not been characterized.

The other part of the discovery is can we find variants in this what was thought to be desert landscape of the genome, which actually probably plays an important role in the regulation of the ion channels that we know cause these sudden death disorders.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.