Genomic Autopsy of Sudden Deaths in Young Individuals

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.

Figure 1.. Distribution of Diagnoses and Age at Death Among 103 Cases of Sudden Death in Young Individuals

A, Cases were divided into 3 major diagnostic categories based on autopsy and histology. All percentages are based on the total number of decedents (N = 103). In 2 cases, premortem clinical data were diagnostic for a channelopathy but had not been recognized before death (1 long QT syndrome and 1 catecholaminergic polymorphic ventricular tachycardia). Cardiomyopathy includes all cases that met criteria for cardiomyopathy but did not fit into a single phenotype. B, Genetic variant classification, stratified by age at death. Each decedent was classified based on the most pathogenic variant identified. Fewer referrals were derived from the 6- to 10-year-old group. Decedents between age 41 and 45 years were analyzed only for the first 6 months of the study. AVC indicates arrhythmogenic ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy.

Figure 2.. Number of Variants Associated With Age at Death Suggesting Oligogenic Inheritance

A, Heat map of weighted missense variants of uncertain significance (VUS). VUSs were identified from a panel of 118 cardiomyopathy and arrhythmia genes plus 30 additional preliminary evidence genes. The number of missense VUSs were corrected for gene length and the gene’s missense z score.^, Genes were ranked by their weighted number of missense VUS. The highest-ranking 35 genes are shown (of the 78 genes with at least 1 curated VUS); higher values are represented by darker shades. The total number of VUSs contributing to each row of analysis is annotated to the right. B, The number of variants in comprehensive cardiac gene panel, or curated variants, was regressed against age at death. Curated variant number was significantly associated with earlier age at death (P = .001, corrected for autopsy phenotype, genetic ancestry, and sex). For this age-variant burden analysis, 11 decedents younger than 2 years were excluded to avoid the environmental contributions that can confound analysis of sudden death in this age group. ^aGenes with 1 or more loss of function variants.