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Original Investigation
August 11, 2021

Genomic Autopsy of Sudden Deaths in Young Individuals

Author Affiliations
  • 1Division of Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
  • 2Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 3Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 4Center for Genetic Medicine, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 5Cook County Medical Examiner’s Office, Chicago, Illinois
  • 6Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
  • 7Section Editor, JAMA Cardiology
JAMA Cardiol. 2021;6(11):1247-1256. doi:10.1001/jamacardio.2021.2789
Key Points

Question  Can genomic analysis improve clinical care for families after a sudden death in young individuals?

Findings  In this cohort study of 103 decedents from a national collaboration of medical examiners, pathogenic/likely pathogenic variants in arrhythmia or cardiomyopathy genes were identified in 13%. In multivariate analysis, rare variants in cardiac genes (pathogenic/likely pathogenic/uncertain significance) were associated with younger age at death.

Meaning  Genomic autopsy found clinically actionable cardiac variants in 13% of sudden deaths in young individuals, but a more sophisticated model of multiple gene effects or oligogenic model may be required to optimize clinical care for families.

Abstract

Importance  Postmortem genetic testing of young individuals with sudden death has previously identified pathogenic gene variants. However, prior studies primarily considered highly penetrant monogenic variants, often without detailed decedent and family clinical information.

Objective  To assess genotype and phenotype risk in a diverse cohort of young decedents with sudden death and their families.

Design, Setting, and Participants  Pathological and whole-genome sequence analysis was conducted in a cohort referred from a national network of medical examiners. Cases were accrued prospectively from May 2015 to March 2019 across 24 US states. Analysis began September 2016 and ended November 2020.

Exposures  Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation.

Results  A total of 103 decedents (mean [SD] age at death, 23.7 [11.9] years; age range, 1-44 years), their surviving family members, and 140 sex- and genetic ancestry–matched controls were analyzed. Among 103 decedents, autopsy and clinical data review categorized 36 decedents with postmortem diagnoses, 23 decedents with findings of uncertain significance, and 44 with sudden unexplained death. Pathogenic/likely pathogenic (P/LP) genetic variants in arrhythmia or cardiomyopathy genes were identified in 13 decedents (12.6%). A multivariable analysis including decedent phenotype, ancestry, and sex demonstrated that younger decedents had a higher burden of P/LP variants and select variants of uncertain significance (effect size, −1.64; P = .001). These select, curated variants of uncertain significance in cardiac genes were more common in decedents than controls (83 of 103 decedents [86%] vs 100 of 140 controls [71%]; P = .005), and decedents harbored more rare cardiac variants than controls (2.3 variants per individual vs 1.8 in controls; P = .006). Genetic testing of 31 parent-decedent trios and 14 parent-decedent dyads revealed 8 transmitted P/LP variants and 1 de novo P/LP variant. Incomplete penetrance was present in 6 of 8 parents who transmitted a P/LP variant.

Conclusions and Relevance  Whole-genome sequencing effectively identified P/LP variants in cases of sudden death in young individuals, implicating both arrhythmia and cardiomyopathy genes. Genomic analyses and familial phenotype association suggest potentially additive, oligogenic risk mechanisms for sudden death in this cohort.

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