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）：青少年猝死（SDY）是一种悲惨事件，会给家庭带来毁灭性的后果，他们必须承受孩子的意外失去，以及可能患有威胁其他成员健康和生存的家庭疾病。由于缺乏证据，科学界对于预防 SDY 的最佳方法几乎没有达成共识。因此，国家心肺血液研究所 (NHLBI)、国家神经疾病和中风研究所 (NINDS) 以及疾病控制和预防中心 (CDC) 通过获取详细的临床信息并存档美国各地 SDY 病例的 DNA 样本，对 SDY 病例登记处进行了大量投资，目的是确定 SDY 的基因组和机制基础。我们建议将犹他州 SDY 中心建立为 SDY 注册中心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、资源以及合作基础设施来实现注册中心的目标。我们的提案解决了 SDY 研究领域的几个关键障碍：1）标准基因测试无法识别大多数尸检阴性 SDY 的分子原因； 2）当前策略未验证已识别变体的功能； 3) 尽管有 I 类专家共识建议，但综合家庭心脏评估的执行不一致。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，以便利用全外显子组/基因组测序发现尸检阴性 SDY 的基因组基础。具体目标 2：使用基于细胞和模型生物的测定来表征新的 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、基因型、风险分层并为幸存家庭成员提供咨询。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。