Channelopathies and Cardiomyopathies Among Sudden Deaths in the Young

 描述(由申请人提供)：不明原因猝死(SUD)在任何年龄都是一件悲惨的事情。1-35岁年龄段的SUD发病率为每10万人年1-3次。除了生命损失外，SUD可能预示着存活的一级亲属猝死的风险增加。大约25%的SUD病例被归咎于心率(例如，通道病)和心肌功能(例如，心肌病)的遗传性疾病。筛查SUD患者的一级亲属是否患有遗传病，可能会发现更多有猝死风险的家庭成员。我们建议进行一项三层研究，旨在揭示由青年猝死(SDY)病例登记处收集的猝死病例中通道病和心肌病的患病率和突变谱，这些病例发生在没有癫痫的情况下，并且有很高的心脏病因学可能性。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有针对性的生物信息学分析。全基因组测序产生比外显子测序更一致的编码序列覆盖范围，并提供机会来研究非编码变异的分析。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SCN5A、KCNQ1和KCNH2。这些实验将产生至关重要的数据，以确定一大类易患SUD的预期变异的致病可能性。最后，在特定的目标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的致病变异从父母那里遗传而不是从头产生的频率。确定SUD病例中传播突变与新发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，我们还将通过我们与芝加哥和伊利诺伊州周边县的法医办公室的现有合作，识别新的SDY病例，从而增加登记的价值，并确保可在整个研究网络中共享的SDY病例的强劲增长。

 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.