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.

重要性 对猝死的年轻个体的死后基因检测先前已经确定了致病基因变异。然而，先前的研究主要考虑高度外显的单基因变异，通常没有详细的死者和家庭临床信息。

目的 评估不同队列的猝死年轻死者及其家人的基因型和表型风险。

设计、设置和参与者 病理和全基因组序列分析在来自全国体检医师网络的队列中进行。从 2015 年 5 月到 2019 年 3 月，美国 24 个州的病例前瞻性累积。分析从 2016 年 9 月开始，到 2020 年 11 月结束。

暴露 评估与全基因组序列数据和家庭成员评估相结合的尸检和临床数据。

结果 共分析了 103 名死者（平均 [SD] 死亡年龄，23.7 [11.9] 岁；年龄范围，1-44 岁）、他们在世的家庭成员以及 140 名性别和遗传血统匹配的对照。在 103 名死者中，尸检和临床数据审查将 36 名死者诊断为死后诊断，23 名死者发现意义不确定，44 名死于不明原因的突然死亡。在 13 名死者 (12.6%) 中发现了心律失常或心肌病基因的致病性/可能致病性 (P/LP) 遗传变异。包括死者表型、血统和性别在内的多变量分析表明，年轻死者的 P/LP 变体负担更高，并且选择了意义不确定的变体（效应大小，-1.64；P = .001)。这些在心脏基因中具有不确定意义的精选变异在死者中比对照组更常见（103 名死者中的 83 名 [86%] vs 140 名对照中的 100 名 [71%]；P  = .005），死者携带更罕见的心脏变异比对照组（每个个体 2.3 个变体，对照组 1.8 个变体；P  = .006）。对 31 个亲代三重奏和 14 个亲代-死代二元组的基因检测揭示了 8 个传播的 P/LP 变体和 1 个从头 P/LP 变体。传播 P/LP 变异的 8 名父母中有 6 名存在不完全外显率。

结论和相关性 全基因组测序有效地鉴定了年轻人猝死病例中的 P/LP 变异，这涉及心律失常和心肌病基因。基因组分析和家族表型关联表明该队列中猝死的潜在加性、寡基因风险机制。