When death occurs suddenly and unexpectedly, the underlying causes may remain in doubt, even after a traditional clinical autopsy. To bring hidden causes to light, medical examiners may want to consider molecular autopsies, which can probe more deeply than any scalpel, dissecting the deceased’s genome for potentially deleterious mutations. Should such mutations be found, the deceased’s family members could be duly informed of their own risks and how to minimize them.
The potential value of molecular autopsies was evaluated in a study led by scientists at The Scripps Research Institute (TSRI) and the Scripps Translational Science Institute (STSI). These scientists, led by Ali Torkamani, Ph.D., an assistant professor of molecular medicine at TSRI and the director of Genome Informatics at STSI, report that molecular autopsies may be used to reveal gene mutations responsible for sudden deaths.
“The key takeaway,” said Dr. Torkamani, “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.”
Details of the TSRI/STSI study appeared October 11 in the Journal of the American Medical Association (JAMA), in a research letter entitled, “Molecular Autopsy for Sudden Unexpected Death.” The letter summarized the results obtained after exome sequencing tests were performed on blood or tissue samples collected from deceased persons aged 45 year or younger. All the deceased had experienced sudden, unexpected death. All the cases were referred to STSI by the medical examiner. In several cases, exome sequencing was also performed on saliva samples from parents.
For the study, the researchers sequenced samples from 25 sudden death cases. To assess possible inherited mutations, the team also sequenced samples from the deceased patients' parents in nine of the cases.
This analysis provided clues that weren't apparent in traditional clinical autopsies. In four cases, the researchers found that a genetic mutation was a “likely” cause of death, and they found six more cases where a mutation was a “plausible” cause of death. In seven cases, a mutation was found to be a “speculative” cause of death.
Overall, molecular autopsies uncovered a likely or plausible cause of death in 40% of cases. Interestingly, many of the findings were variants of genes inherited from relatives who had not suffered from the syndrome.
“Although this study is limited by its small sample size and potentially by selection bias, the observation of likely and plausible pathogenic variants in unaffected relatives is consistent with recent large-scale studies that identified clinically relevant variants in living relative of sudden cardiac death [SCD] cases,” wrote the authors of the JAMA study. “Our study suggests that similar findings may be observed in non-SCD sudden deaths.”
Sudden death strikes approximately 11,000 people under age 45 in the United States every year from conditions including sudden infant death, pulmonary embolism, rupture aortic aneurysm, and SCD. Such causes may not be established even if clinical autopsies are performed. Clinical autopsies, in any event, are being performed less frequently.
“It should be noted that these speculative and plausible findings cannot definitely be linked to sudden death,” the authors explained. “The ambiguity associated with some of these genetic findings should be balanced against the potential for clinical follow-up, active surveillance, or preventive interventions in living relatives.” Finally, the authors emphasized that larger studies are needed to collect enough data to provide living relatives with a better idea of their risk.