Integrating Genomic and Clinical Approaches to Sudden Death in the Young

 描述(申请人提供)：幼年猝死(SDY)是一件悲剧性的事件，对家庭来说是毁灭性的后果，他们必须忍受意外失去孩子的后果，以及可能存在威胁其余成员健康和生存的家庭障碍。由于缺乏证据，科学界对预防SDY的最佳方法几乎没有达成共识。因此，国家心、肺和血液研究所(NHLBI)、国家神经疾病和中风研究所(NINDS)和疾病控制和预防中心(CDC)通过获取详细的临床信息和归档全美SDY病例的DNA样本，在SDY病例登记中进行了广泛的投资，目的是确定SDY的基因组和机制基础。我们建议建立犹他州SDY中心作为SDY注册中心不可或缺的合作伙伴，提供无与伦比的生物信息学、基因组学和临床专业知识、资源和协作基础设施，以实现注册中心的目标。我们的建议解决了SDY研究领域的几个关键障碍：1)标准基因测试未能在大多数尸检阴性的SDY中确定分子原因；2)当前的策略没有验证已识别的变体的功能；3)尽管I类专家一致建议，但仍无法进行全面的家庭心脏评估。我们建议通过实现以下目标来克服这些障碍：具体目标1：向SDY病例登记处提供生物信息学专业知识，使其能够利用全外显子组/基因组测序发现尸检阴性SDY的基因组基础。具体目标2：利用基于细胞和模型生物体的分析，鉴定新的SDY疾病基因、等位基因和疾病机制。具体目标3：将我们在SDY方面的临床专业知识整合到表型、基因、风险分层和建议幸存的家庭成员。犹他州SDY中心的多学科研究计划将使我们能够以前所未有的规模和分辨率发现、验证和表征新的猝死基因、等位基因和机制。通过与其他SDY病例登记中心的合作，犹他州中心将促进对SDY的机械性理解，从而为未来的筛查战略和预防措施奠定基础。

 DESCRIPTION (provided by applicant): Sudden death in the young (SDY) is a tragic event, with devastating consequences for the family who must endure both the unexpected loss of their child and the possibility of harboring a familial disorder that threatens the health and survival of the remaining members. Due to lack of evidence, there is little consensus within the scientific community around the best method for preventing SDY. Thus, the National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurologic Disorders and Stroke (NINDS) and Centers for Disease Control and Prevention (CDC) have invested extensively in the SDY Case Registry by acquiring detailed clinical information and archiving DNA samples from SDY cases across the United States, with the goal of defining the genomic and mechanistic basis for SDY. We propose to establish the Utah SDY Center as an integral partner of the SDY Registry, by providing unparalleled bioinformatics, genomics and clinical expertise, resources, and an infrastructure for collaboration to accomplish the Registry's goals. Our proposal addresses several critical barriers in the field of SDY research: 1) standard genetic testing fails to identify a molecular cause in the majority of autopsy-negative SDY; 2) current strategies do not validate the functionality of identified variants; and 3) a comprehensive family cardiac evaluation is inconsistently performed despite Class I expert consensus recommendations. We propose to overcome these barriers by achieving the following Aims: Specific Aim 1: Provide the SDY Case Registry with the bioinformatics expertise that will enable the discovery of the genomic basis for autopsy-negative SDY, using whole-exome/genome sequencing. Specific Aim 2: Characterize novel SDY disease genes, alleles and disease mechanisms, using cell- and model organism-based assays. Specific Aim 3: Integrate our clinical expertise in SDY to phenotype, genotype, risk-stratify and counsel surviving family members. The Utah SDY Center's multi-disciplinary research plan will allow us to discover, validate and characterize new sudden death genes, alleles and mechanisms at a scale and resolution not previously possible. By partnering with other SDY Case Registry Centers, the Utah Center will promote a mechanistic understanding of SDY and thus establish the foundation for future screening strategies and preventative measures.