Molecular Autopsy Finds Cause in Cases of Sudden Death

Jennifer Garcia

October 12, 2016

Molecular autopsy may be useful in uncovering a likely or plausible cause of death in cases of sudden unexpected death, according to findings of a prospective study published in the October 11 issue of JAMA.

"Molecular autopsy was able to uncover a likely or plausible cause of death in 40% of cases (10/25)," and "has the potential to provide more accurate family health information to a wider spectrum of afflicted families," the authors write.

Ali Torkamani, PhD, from the Scripps Translational Science Institute, La Jolla, California, and colleagues performed exome sequencing on blood and tissue samples from 25 patients, aged 45 years or younger, who died unexpectedly. Clinical autopsy identified a likely cause of death

The patients were referred to the authors' facility by the medical examiner between October 2014 and November 2015. The authors excluded patients with known comorbid conditions or external cause of death from the current analysis. In nine cases, sequencing was also performed on saliva samples from both parents.

The researchers categorized mutations as "likely cause of death (mutation previously reported or expected in an [sudden cardiac death (SCD)]-related gene); plausible cause of death (mutation of unknown significance in an SCD gene); or speculative cause of death (mutation previously reported in other disorders)."

Using genome sequencing and analysis, the researchers 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 7 cases (28%). Corroboration with clinical autopsy findings was possible in two cases with a likely genetic cause of death, and in three cases with a plausible or speculative cause. No mutations were identified in eight cases (32%).

Further, the authors found that in 70% of cases (7/10) with likely or plausible genetic cause of death, the pathogenic mutations were inherited from relatives with no history of sudden death.

"Sudden death in a family member can create ambiguity as to the cause of death and/or whether family members are at risk; molecular autopsy has the potential to solve both of these issues," noted Dr Torkamani in an interview with Medscape Medical News.

In their study, the authors note that clinical autopsy rates have dropped below 10% as of 2008. When asked about the value of molecular autopsy in this setting, Dr Torkamani replied: "I believe molecular autopsy solves a couple of issues facing clinical autopsies: 1) the cost of genetic testing is dropping and could offset some of the concerns about the cost of clinical autopsies — especially if a benefit for living relatives can be shown, then there is some potential for coverage by insurers; and 2) many living relatives are reluctant to consent to an invasive procedure like a clinical autopsy, whereas a molecular autopsy is noninvasive and potentially more palatable to living relatives."

The authors acknowledge that small sample size and possible selection bias are limitations of the study; however, they note that these findings are consistent with recent large-scale studies among patients with SCD.

"About 300,000 to 400,000 deaths per year in the US are due to conditions that can cause sudden death. A coordinated molecular autopsy program would improve our understanding of the genetics surrounding these conditions," noted Dr Torkamani.

Funding for this study was provided by an award from the National Institutes of Health and National Center for Advancing Translational Sciences and grants from Scripps Genomic Medicine. The authors have disclosed no relevant financial relationships.

JAMA. 2016;316:1492-1494. Extract

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