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（由适用提供）：突然意外死亡（SUD）是任何年龄段的悲惨事件。 1至35岁之间的SUD事件是每100,000人年的1-3事件。除了生命损失外，SUD可能会使生存一级亲戚的猝死风险增加。心律的遗传疾病（例如通道病）和心肌功能（例如心肌病）被斑驳约25％的SUD病例。筛选遗传疾病的SUD受害者的一级亲戚可能会发现其他有猝死风险的家庭成员。我们提出了一项三层研究研究，旨在揭示通道病和心肌病的患病率和突变谱，这是由于没有癫痫病并且患有心脏病学可能很高的年轻人（SDY）病例注册中突然死亡而收集的突然死亡的病例。在特定的目标1中，我们建议对500例SDY病例进行全基因组测序，并对具有已知参与的先天性心律失常敏感性或遗传性心肌病的靶向生物信息学分析。整个基因组测序比外显子组测序产生的编码序列覆盖范围更大，并提供了能够研究非编码变化的机会。在特定的目标2中，我们建议进行实验，以阐明心脏离子通道基因（尤其是SCN5A，KCNQ1和KCNH2）中与SDY相关遗传变异的功能后果。这些实验将生成对于分配大量预期变体的致病可能性所必需的数据。最后，在特定的目标3中，我们将确定与先天心律失常易感性和心肌病有关的基因中的致病变异频率是从父母那里遗传而非从头开始的。确定在SUD病例中的传播与从头突变的速度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，我们还将通过与伊利诺伊州芝加哥和周边县的医学检查员办事处的现有合作来确定新的SDY案例，从而为注册表增加了价值，并确保可以在整个研究网络中共享SDY案例的良好准确性。