Division of Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
JAMA Cardiol. 2021 Nov 1;6(11):1247-1256. doi: 10.1001/jamacardio.2021.2789.
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.
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.
Evaluation of autopsy and clinical data integrated with whole-genome sequence data and family member evaluation.
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.
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.
对突然死亡的年轻个体进行死后基因检测先前已确定了致病性基因突变。然而，先前的研究主要考虑了高度外显的单基因变异，且通常缺乏详细的死者和家族临床信息。
评估具有突然死亡的年轻死者及其家族的基因型和表型风险。
设计、地点和参与者：对从全国法医网络转介的队列进行了病理和全基因组序列分析。该队列从 2015 年 5 月至 2019 年 3 月在美国 24 个州前瞻性入组。分析于 2016 年 9 月开始，2020 年 11 月结束。
评估尸检和临床数据，结合全基因组序列数据和家族成员评估。
共分析了 103 名死者（死亡时的平均[SD]年龄，23.7[11.9]岁；年龄范围，1-44 岁）、其幸存的家庭成员和 140 名性别和遗传祖先匹配的对照者。在 103 名死者中，通过尸检和临床数据回顾将 36 名死者归类为有死后诊断，23 名死者为有不确定意义的发现，44 名死者为突然不明原因死亡。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）基因突变。包括死者表型、遗传起源和性别在内的多变量分析表明，年轻死者的 P/LP 变异和某些不确定意义的变异负担更高（效应大小，-1.64；P = .001）。这些在心脏基因中经选择、精心评估的不确定意义的变异在死者中比对照组更常见（103 名死者中有 83 例[86%] vs 140 名对照者中有 100 例[71%]；P = .005），且死者携带的罕见心脏变异比对照组更多（每个个体 2.3 个变异 vs 对照组 1.8 个；P = .006）。对 31 个父母-死者三胞胎和 14 个父母-死者二联体进行的基因检测显示，有 8 个传递的 P/LP 变异和 1 个新出现的 P/LP 变异。在传递 P/LP 变异的 8 位父母中，有 6 位存在不完全外显率。
全基因组测序有效地鉴定了年轻个体突然死亡病例中的 P/LP 变异，提示心律失常和心肌病基因均参与其中。基因组分析和家族表型相关性表明，该队列中存在潜在的、多基因的突然死亡风险机制。
