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Pathologists Performing Molecular Autopsy in Cases of Sudden Unexpected Death Could Identify Genetic Clues That Help Surviving Family Members Assess Their Own Risk

Pathologists could benefit if postmortem genetic testing becomes more commonplace following incidents of sudden unexpected death

Pathologists are discovering that molecular autopsy, also called postmortem molecular testing, could boost the chance of discovering the likely or plausible cause of sudden unexpected death, according to preliminary results from a study published in the Journal of the American Medical Association (JAMA).

Researchers led by Ali Torkamani, PhD, Director of Genome Informatics at the Scripps Translational Science Institute (STSI) and Assistant Professor of Molecular and Experimental Medicine at the Scripps Research Institute, sequenced samples from 25 sudden death cases. They identified:

• A likely cause of death in four cases (16%);

• A plausible cause of death in six cases (24%); and

• A speculative cause of death in seven cases (28%).

Clinical autopsies corroborated their findings with a likely genetic cause of death in two cases, and with a plausible or speculative cause in three cases. No mutations were found in eight cases (32%).

In only three of 10 causes did the researchers determine that pathogenic mutations inherited from relatives with a history of sudden death were the likely or plausible genetic cause of death.

Determining Genetic Cause of Death Critical for Relatives of Deceased

Unexpected deaths of young adults (under age 45) and infants occur roughly 11,000 times each year from a range of conditions such as:

Sudden infant death syndrome;

Pulmonary embolism;

Ruptured aortic aneurysm; and

Cardiac arrest.

Often a cause of death is not determined, leaving living relatives with an “inaccurate or ambiguous family health history,” Torkamani and colleagues wrote in a research letter published in JAMA.

“The key takeaway is that molecular autopsy, when performed in a prospective and family-based manner, can reveal the genetic cause of sudden death in a variety of conditions and provide useful information regarding risk to living relatives,” Torkamani said in an STSI news release.

Ali Torkamani, PhD (above) notes a gene mutation in the data displayed. Torkamani is Director of Genome Informatics at the Scripps Translational Science Institute and Assistant Professor of Molecular and Experimental Medicine at the Scripps Research Institute. (Photo copyright: Roland Lizarondo/KPBS.)

Ali Torkamani, PhD (above) notes a gene mutation in the data displayed. Torkamani is Director of Genome Informatics at the Scripps Translational Science Institute and Assistant Professor of Molecular and Experimental Medicine at the Scripps Research Institute. (Photo copyright: Roland Lizarondo/KPBS.)

In a commentary published in the January 17, 2017, issue of JAMA, Steven Schrodi, PhD, Associate Research Scientist at the Center for Human Genetics, Marshfield Clinic Research Foundation, suggested that Torkamani’s study “could greatly benefit from a more rigorous statistical framework,” which could be achieved by passing healthy control data through the Scripps Idiopathic Diseases In Man (IDIOM) analysis pipeline. This additional step would allow Torkamani to assess the false positive rate for his study, Schrodi noted.

JAMA editors included a response from Torkamani in the January 17 issue in which he agreed that there “remains a large degree of uncertainty between the observation of rare pathogenic variants for rare diseases and their ultimate attribution as the cause of sudden death.” Torkamani also noted the study labeled these potential connections as “speculative.”

Torkamani wrote, “They should not be interpreted as the genetic cause of death with any degree of certainty …. Rather, the intent was to highlight potential expansions derived from exome sequencing to genetic causes of sudden death beyond the usual suspects [genes related to sudden cardiac death] that are typically included in clinical panel-based testing.”

Ethical Concerns About Genetic Autopsies

While researchers acknowledge more studies are needed to confirm postmortem genetic testing’s ability to find clues to sudden death, they are confident that doing so could help doctors and family members plan for clinical follow-ups, preventative measures, and active surveillance to watch for symptoms—even in cases where mutation was a “speculative” cause of death, the Scripps Research Institute pointed out in its news release.

Torkamani told Medscape Medical News that, given the number of deaths occurring each year due to conditions that can cause sudden death, “A coordinated molecular autopsy program would improve our understanding of the genetics surrounding those conditions.”

However, an article in The Atlantic suggested that routine use of molecular autopsies in cases of sudden death has its detractors, due in part to ethical concerns. “Family members, in looking for an explanation for their grief, might end up finding unsettling things about themselves,” staff writer Sarah Zhang noted about genetic autopsies. “What medical advice do you give someone carrying the same ticking genetic time bomb that killed their loved one? And who is responsible for telling the family?”

An upward trend in the number of molecular autopsies performed each year would directly benefit pathologists, who could offer postmortem genetic testing services in their communities. Since such testing would not be covered by health insurance, this cash-only service not only would benefit a pathology group’s bottom line, but also provide another example of molecular and genetic analysis advancing knowledge in medicine.

—Andrea Downing Peck

Related Information:

Molecular Autopsy for Sudden Unexpected Death

Post-Mortem Genetic Testing for Sudden Unexpected Death

Post-Mortem Genetic Testing for Sudden Unexpected Death–Reply

TSRI and STSI Scientists Use ‘Molecular Autopsies’ to Find Clues to Sudden Death

Molecular Autopsy Finds Cause in Cases of Sudden Death

When Genetic Autopsies Go Awry

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