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Molecular autopsy offers insight into sudden cardiac death risk
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Sudden unexpected death occurs in an estimated 11,000 people aged younger than 45 years in the United States each year. A comprehensive molecular autopsy program could potentially provide more detailed and accurate health information for families affected by sudden unexpected death.
Common conditions related to sudden unexpected death include sudden cardiac death, sudden infant death, pulmonary embolism and ruptured aortic aneurysm, Ali Torkamani, PhD, assistant professor and director of drug discovery at Scripps Translational Science Institute, and colleagues wrote in a research letter published in JAMA. “Sometimes the cause of death is not determined, even after clinical autopsy, leaving living relatives with an inaccurate or ambiguous family health history.”
Moreover, the researchers noted there has been a decline in the rate of clinical autopsies in the past 50 years, from about 50% to less than 10% in 2008.
“This uncertainty may be partially resolved with postmortem genetic testing (‘molecular autopsy’)”, the researchers wrote. “Initial studies, limited to cardiac channelopathy and epilepsy genes, have yielded molecular diagnoses in approximately 25% of cases.”
Torkamani and colleagues conducted a systematic, prospective, family based, molecular autopsy study using exome sequencing on collected blood and tissue samples from patients 45 years and younger with sudden unexpected death. All were referred to Scripps Translational Science Institute by a medical examiner from October 2014 to November 2015. If available, exome sequencing was also performed on saliva swabs from parents of the deceased.
The researchers sequenced 25 cases, of which nine included both parents of the deceased. The majority (80%) were men.
The researchers determined that clinical autopsy “discovered the likely cause of death in five cases.” Mutations identified by molecular autopsy were categorized as:
- a likely cause of death (four cases; 16%);
- a plausible cause of death (six cases; 24%); or
- a speculative cause of death (seven cases; 28%).
In eight cases (32%), no mutations were identified.
Those categorized as a likely cause of death were mutations previously reported/expected in a gene related to sudden cardiac death; those categorized as a plausible cause of death were mutations of unknown significance in a sudden cardiac death gene; and those categorized as a speculative cause of death were mutations reported previously in other disorders, according to the research letter.
In two of five cases, the clinical autopsy findings were corroborated with the likely genetic cause of death, whereas in the other three cases the clinical autopsy findings were linked to plausible or speculative genetic causes, the researchers wrote.
In seven of 10 cases with likely or plausible mutations, the mutations were inherited by relatives who did not have a sudden unexpected death, according to the findings.
“Molecular autopsy was able to uncover a likely or plausible cause of death in 40% of cases. … 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 relatives of sudden cardiac death cases,” Torkamani and colleagues wrote.
The researchers noted several limitations of this study, including a small sample size and selection bias.
“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. Although molecular autopsies may help identify genetic causes of sudden unexpected death, a comprehensive and systematic effort to collect and share genetic and phenotypic data is needed to more precisely defined pathogenic variants and provide quantifiable risks to living relatives,” they wrote. – by Dave Quaile
Disclosure: One researcher reports receiving grants from Bundesministerium für Bildung und Forschung and Deutsche Forschungsgemeinschaft and personal fees from Lundbeck and Pfizer. The other researchers report no relevant financial disclosures.
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