Puckelwartz Megan J, Pesce Lorenzo L, Hernandez Edgar J, Webster Gregory, Dellefave-Castillo Lisa M, Russell Mark W, Geisler Sarah S, Kearns Samuel D, Etheridge Felix K, Etheridge Susan P, Monroe Tanner O, Pottinger Tess D, Kannankeril Prince J, Shoemaker M Benjamin, Fountain Darlene, Roden Dan M, MacLeod Heather, Burns Kristin M, Yandell Mark, Tristani-Firouzi Martin, George Alfred L, McNally Elizabeth M
medRxiv. 2023 Mar 29:2023.03.27.23287711. doi: 10.1101/2023.03.27.23287711.
Sudden unexpected death in children is a tragic event. Understanding the genetics of sudden death in the young (SDY) enables family counseling and cascade screening. The objective of this study was to characterize genetic variation in an SDY cohort using whole genome sequencing.
The SDY Case Registry is a National Institutes of Health/Centers for Disease Control surveillance effort to discern the prevalence, causes, and risk factors for SDY. The SDY Case Registry prospectively collected clinical data and DNA biospecimens from SDY cases <20 years of age. SDY cases were collected from medical examiner and coroner offices spanning 13 US jurisdictions from 2015-2019. The cohort included 211 children (mean age 1 year; range 0-20 years), determined to have died suddenly and unexpectedly and in whom DNA biospecimens and next-of-kin consent were ascertained. A control cohort consisted of 211 randomly sampled, sex-and ancestry-matched individuals from the 1000 Genomes Project. Genetic variation was evaluated in epilepsy, cardiomyopathy and arrhythmia genes in the SDY and control cohorts. American College of Medical Genetics/Genomics guidelines were used to classify variants as pathogenic or likely pathogenic. Additionally, genetic variation predicted to be damaging was identified using a Bayesian-based artificial intelligence (AI) tool.
The SDY cohort was 42% European, 30% African, 17% Hispanic, and 11% with mixed ancestries, and 39% female. Six percent of the cohort was found to harbor a pathogenic or likely pathogenic genetic variant in an epilepsy, cardiomyopathy or arrhythmia gene. The genomes of SDY cases, but not controls, were enriched for rare, damaging variants in epilepsy, cardiomyopathy and arrhythmia-related genes. A greater number of rare epilepsy genetic variants correlated with younger age at death.
While damaging cardiomyopathy and arrhythmia genes are recognized contributors to SDY, we also observed an enrichment in epilepsy-related genes in the SDY cohort, and a correlation between rare epilepsy variation and younger age at death. These findings emphasize the importance of considering epilepsy genes when evaluating SDY.
儿童意外猝死是一个悲剧性事件。了解年轻人猝死（SDY）的遗传学知识有助于进行家庭咨询和级联筛查。本研究的目的是使用全基因组测序来表征SDY队列中的遗传变异。
SDY病例登记处是美国国立卫生研究院/疾病控制中心的一项监测工作，旨在了解SDY的患病率、病因和风险因素。SDY病例登记处前瞻性地收集了年龄小于20岁的SDY病例的临床数据和DNA生物样本。2015年至2019年期间，从美国13个司法管辖区的法医和验尸官办公室收集了SDY病例。该队列包括211名儿童（平均年龄1岁；范围0至20岁），这些儿童被确定为意外猝死，并且已获取DNA生物样本和近亲同意书。一个对照队列由来自千人基因组计划的211名随机抽样、性别和血统匹配的个体组成。在SDY队列和对照队列中评估了癫痫、心肌病和心律失常基因中的遗传变异。使用美国医学遗传学/基因组学学会的指南将变异分类为致病性或可能致病性。此外，使用基于贝叶斯的人工智能（AI）工具识别预测具有损害性的遗传变异。
SDY队列中42%为欧洲血统，30%为非洲血统，17%为西班牙裔，11%为混合血统，39%为女性。该队列中有6%的人在癫痫、心肌病或心律失常基因中携带致病性或可能致病性的遗传变异。SDY病例的基因组而非对照的基因组在癫痫、心肌病和心律失常相关基因中富含罕见的、具有损害性的变异。更多罕见的癫痫遗传变异与死亡时更年轻的年龄相关。
虽然已知具有损害性的心肌病和心律失常基因是SDY的促成因素，但我们在SDY队列中也观察到癫痫相关基因的富集，以及罕见癫痫变异与死亡时更年轻年龄之间的相关性。这些发现强调了在评估SDY时考虑癫痫基因的重要性。
