Channelopathies and Cardiomyopathies Among Sudden Deaths in the Young

年轻人猝死中的通道病和心肌病

• 批准号: 9242061
• 负责人: Alfred L. George
• 金额: $ 82.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242061
• 关键词: Absence Epilepsy; Age; Arrhythmia; Autopsy; Bioinformatics; Cardiac; Cardiomyopathies; Cessation of life; Chicago; Child; Clinical Data; Code; Collaborations; Computer Simulation; Congenital cardiomyopathy; Costs and Benefits; Counseling; County; Coupled; DNA; Data; Data Analyses; Deposition; Drug Exposure; Electrophysiology (science); Ensure; Epilepsy; Etiology; Event; Exposure to; Family; Family member; First Degree Relative; Frequencies; Future; Gene Frequency; General Population; Genes; Genetic; Genetic Predisposition to Disease; Gold; Heart Diseases; Hereditary Disease; Human Genome; Illinois; Incidence; Inherited; Ion Channel; Laboratories; Life; Long QT Syndrome; Medical Examiners; Molecular; Mutation; Myocardial; Parents; Pathogenesis; Pathogenicity; Persons; Pharmacology; Population Control; Predisposition; Prevalence; Probability; Property; Protocols documentation; Public Health; Registries; Research; Research Design; Resources; Risk; Scheme; Sudden Death; Testing; Variant; Work; case control; cooking; data registry; design; exome sequencing; experimental study; genetic variant; genome sequencing; genomic data; heart rhythm; innovation; next generation sequencing; novel; public health relevance; research study; screening; supercomputer; variant of unknown significance; whole genome; young adult

 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.

 描述（由申请人提供）： 不明原因猝死 (SUD) 在任何年龄段都是一种悲剧事件，除了死亡之外，1 岁至 35 岁之间的 SUD 发病率是每 10 万人每年发生 1-3 起。 ，SUD 可能预示着幸存的一级亲属的猝死风险增加。大约 25% 的 SUD 病例归咎于心脏病（例如心肌病）。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。青少年猝死 (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，这些猝死发生在没有癫痫的情况下，并且很有可能在特定目标 1 中，我们建议对 500 个 SDY 病例进行全基因组测序，并对已知与先天性心律失常易感性或遗传性心肌病有关的基因进行有针对性的生物信息学分析，以产生更均匀的编码序列覆盖。比外显子组测序更重要，并提供了研究非编码变异的机会。在具体目标 2 中，我们建议进行实验来阐明非编码变异的功能后果。心脏离子通道基因中与 SDY 相关的遗传变异，尤其是 SCN5A、KCNQ1 和 KCNH2，这些实验将生成对于确定一大类易患 SUD 的预期变异的致病性可能性至关重要的数据。确定与先天性心律失常易感性和心肌病变异相关的基因中的致病性从父母遗传的频率，而不是从头产生的频率。 SUD 病例中的新发突变对公共卫生和家庭咨询具有重要影响，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法医办公室的现有合作来识别新的 SDY 病例，从而增加价值。并确保 SDY 案例的稳健累积，并可在研究网络中共享。