Genomic Autopsy of Sudden Deaths in Young Individuals
Genomic Autopsy of Sudden Deaths in Young Individuals
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DOI：
10.1001/jamacardio.2021.2789
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发表时间：
2021-11-01
期刊：
影响因子：
24
通讯作者：
McNally, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Webster, Gregory;Puckelwartz, Megan J.;McNally, Elizabeth M.
重要性：对猝死的年轻个体进行死后基因检测，以前已经确定了致病基因变异。然而，以前的研究主要考虑高渗透性单基因变异，往往没有详细的死者和家庭的临床informations.Objective评估基因型和表型的风险，在一个不同的队列的年轻死者与猝死及其family.DESIGN，SETTTING，和PARTICIPANTS病理和全基因组序列分析进行了一个队列从全国网络的体检医师。从2015年5月到2019年3月，在美国24个州前瞻性地累积了病例。分析开始于2016年9月，结束于2020年11月。EXPOSURES对尸检和临床数据的评估，结合全基因组序列数据和家庭成员评估。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），他们的幸存家庭成员，以及140名性别和遗传祖先匹配的对照。在103名死者中，尸检和临床数据审查将36名死者的尸检诊断，23名死者的发现意义不明，44名死因不明的猝死。在13例（12.6%）死者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。一项包括死者表型、血统和性别的多变量分析表明，年轻死者的P/LP变异负担更高，选择的变异意义不确定（效应量，-1.64; P = .001）。这些在心脏基因中具有不确定意义的选择性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 = 0.005），并且死者比对照组具有更多罕见的心脏变异（每个个体2.3个变异vs对照组1.8个变异; P = 0.006）。对31对父母-死者三人组和14对父母-死者二人组进行基因检测，发现8例遗传性P/LP变异和1例新发P/LP变异。8个父母中有6个传播了P/LP variant.CONCLUSIONS和RELEVANCE全基因组测序有效地确定了P/LP变异的情况下，在年轻人的猝死，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，在这个cohol.IMPORTANCE猝死的年轻人尸检基因检测的潜在的加性，寡基因的风险机制，以前确定了致病基因变异。然而，以前的研究主要考虑高渗透性单基因变异，往往没有详细的死者和家庭的临床informations.Objective评估基因型和表型的风险，在一个不同的队列的年轻死者与猝死及其family.DESIGN，SETTTING，和PARTICIPANTS病理和全基因组序列分析进行了一个队列从全国网络的体检医师。病例从2015年5月至2019年3月在美国24个州进行了前瞻性累积。分析开始于2016年9月，结束于2020年11月。EXPOSURES对尸检和临床数据的评估，结合全基因组序列数据和家庭成员评估。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），他们的幸存家庭成员，以及140名性别和遗传祖先匹配的对照。在103名死者中，尸检和临床数据审查将36名死者的尸检诊断，23名死者的发现意义不明，44名死因不明的猝死。在13例（12.6%）死者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。一项包括死者表型、血统和性别的多变量分析表明，年轻死者的P/LP变异负担更高，选择的变异意义不确定（效应量，-1.64; P = .001）。这些在心脏基因中具有不确定意义的选择性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 = 0.005），并且死者比对照组具有更多罕见的心脏变异（每个个体2.3个变异vs对照组1.8个变异; P = 0.006）。对31对父母-死者三人组和14对父母-死者二人组进行基因检测，发现8例遗传性P/LP变异和1例新发P/LP变异。8个父母中有6个传播了P/LP variant.CONCLUSIONS和RELEVANCE全基因组测序有效地确定了P/LP变异的情况下，在年轻人的猝死，涉及心律失常和心肌病基因。基因组分析和家族表型关联提示该队列中猝死的潜在加性、寡基因风险机制。
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.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.