Channelopathies and Cardiomyopathies Among Sudden Deaths in the Young

 不明原因的猝死（SUD）是任何年龄的悲惨事件。1 - 35岁年龄段SUD的发生率为1-3起事件/100，000人-年。除了生命损失，SUD可能预示着幸存的一级亲属猝死的风险增加。心脏节律的遗传性疾病（例如，通道病）和心肌功能（例如，心肌病）被归咎于大约25%的SUD病例。对SUD受害者的一级亲属进行遗传性疾病筛查可能会发现其他有猝死风险的家庭成员。我们提出了一个三层的研究，旨在揭示的患病率和突变谱的通道病和心肌病的猝死病例中收集的猝死在年轻人（SDY）的情况下，发生在没有癫痫和有很高的可能性有心脏病因。在具体目标1中，我们建议对500例SDY病例进行全基因组测序，并对已知参与先天性心律失常易感性或遗传性心肌病的基因进行靶向生物信息学分析。全基因组测序比外显子组测序产生更均匀的编码序列覆盖，并提供了机会，使非编码变异的分析研究。在具体目标2中，我们建议进行实验以阐明心脏离子通道基因中SDY相关遗传变异的功能后果，特别是SCN 5A，KCNQ 1和KCNH 2。这些实验将产生重要的数据分配的可能性致病性的一大类预期的变异诱发SUD。最后，在具体目标3中，我们将确定与先天性心律失常易感性和心肌病相关的基因中的致病变异从父母遗传而不是从头产生的频率。确定SUD病例中传播与新生突变的比率对公共卫生和家庭咨询具有重要意义。作为我们实验计划的一部分，我们还将通过与芝加哥和伊利诺伊州周边县的医学检查员办公室的现有合作来识别新的SDY病例，从而为登记册增加价值，并确保SDY病例的稳健累积可以在整个研究网络中共享。

 DESCRIPTION (provided by applicant): Sudden unexplained death (SUD) is a tragic event at any age. The incidence of SUD between the ages of 1 and 35 years is 1-3 events per 100,000 person-years. In addition to loss of life, SUD may herald increased risk for sudden death in surviving first-degree relatives. Genetic disorders of heart rhythm (e.g., channelopathies) and myocardial function (e.g., cardiomyopathies) are blamed for approximately 25% of SUD cases. Screening first-degree relatives of a SUD victim for genetic disease may identify additional family members at risk for sudden death. We propose a three-tiered research study designed to uncover the prevalence and mutational spectrum of channelopathies and cardiomyopathies among cases of sudden death collected by the Sudden Death in the Young (SDY) Case Registry that occur in the absence of epilepsy and have a high likelihood of having a cardiac etiology. In Specific Aim 1, we propose to perform whole genome sequencing of 500 SDY cases coupled with targeted bioinformatics analysis of genes with known involvement in congenital arrhythmia susceptibilities or inherited cardiomyopathies. Whole genome sequencing yields more uniform coverage of coding sequences than exome sequencing and offers opportunities to enable studies of analysis of noncoding variation. In Specific Aim 2, we propose to perform experiments to elucidate the functional consequences of SDY-associated genetic variants in cardiac ion channel genes, especially SCN5A, KCNQ1 and KCNH2. These experiments will generate data essential for assigning the likelihood of pathogenicity for a large class of anticipated variants predisposing to SUD. Finally, In Specific Aim 3, we will determine the frequency with which pathogenic variants in genes associated with congenital arrhythmia susceptibility and cardiomyopathy are inherited from a parent rather than arising de novo. Ascertaining the rate of transmitted versus de novo mutations in SUD cases has important implications for public health and family counseling. As part of our experimental plan, we will also identify new SDY cases through our existing collaboration with Medical Examiner's Offices in Chicago and surrounding counties in Illinois, thereby adding value to the registry and ensuring robust accrual of SDY cases that can be shared across the research network.