Integrating Genomic and Clinical Approaches to Sudden Death in the Young

结合基因组学和临床方法治疗年轻人猝死

• 批准号: 9242064
• 负责人: MARTIN TRISTANI-FIROUZI
• 金额: $ 80.63万
• 依托单位: UNIVERSITY OF UTAH
• 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/9242064
• 关键词: Address; Algorithmic Analysis; Alleles; Animal Model; Archives; Arrhythmia; Autopsy; Benchmarking; Bioinformatics; Biological Assay; Biology; CRISPR/Cas technology; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell model; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Code; Collaborations; Communities; Consensus; Counseling; Coupled; DNA; Data; Disease; Electrocardiogram; Electrophysiology (science); Enhancers; Etiology; Evaluation; Event; Face; Familial disease; Family; Family member; Family-Based Registry; Foundations; Future; Genes; Genetic; Genetic Counseling; Genetic screening method; Genome; Genomics; Genotype; Goals; Grief reaction; Health; Heart Diseases; Interdisciplinary Study; International; Ion Channel; Life; Methodology; Methods; Molecular; Mutation; National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; Patch-Clamp Techniques; Pathogenicity; Pathway interactions; Persons; Phenotype; Preventive measure; Public Health; RNA Splicing; Recommendation; Registries; Research; Research Infrastructure; Resolution; Resources; Risk; Risk stratification; Sampling; Site; Societies; Sudden Death; System; Systems Analysis; Testing; United States; Universities; Untranslated RNA; Utah; Variant; Work; Zebrafish; base; candidate validation; disorder prevention; exome; family support; genome analysis; genome editing; genome sequencing; genome-wide; induced pluripotent stem cell; innovation; member; multidisciplinary; novel; precision medicine; premature; prevent; public health relevance; screening; sudden cardiac death; support network; variant of unknown significance

 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.

 描述（由申请人提供）：年轻人猝死（SDY）是一个悲惨的事件，对家庭来说具有毁灭性的后果，他们必须忍受意外失去孩子的痛苦，并可能患有威胁其余成员健康和生存的家族性疾病。由于缺乏证据，科学界对预防SDY的最佳方法几乎没有共识。因此，美国国家心脏、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存档来自美国各地SDY病例的DNA样本，对SDY病例登记进行了广泛的投资，目的是定义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登记处的一个不可或缺的合作伙伴，通过提供无与伦比的生物信息学，基因组学和临床专业知识，资源和合作的基础设施，以实现登记处的目标。我们的提案解决了SDY研究领域的几个关键障碍：1）标准基因检测未能确定大多数尸检阴性SDY的分子原因; 2）目前的策略无法验证已确定变体的功能; 3）尽管I类专家一致建议，但仍不一致地进行全面的家族心脏评估。我们建议通过实现以下目标来克服这些障碍：具体目标1：为SDY病例登记处提供生物信息学专业知识，使其能够使用全外显子组/基因组测序发现尸检阴性SDY的基因组基础。具体目标2：使用基于细胞和模式生物的测定来表征新型SDY疾病基因、等位基因和疾病机制。具体目标3：整合我们在SDY的临床专业知识，以表型，基因型，风险分层和咨询幸存的家庭成员。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病例登记中心合作，犹他州中心将促进对SDY的机械理解，从而为未来的筛查策略和预防措施奠定基础。