Project 2: Genetic Mechanisms of Non-syndromic Congenital Cardiac Defects

项目2：非综合征性先天性心脏缺陷的遗​​传机制

• 批准号: 8231762
• 负责人: Elizabeth Goldmuntz
• 金额: $ 41.63万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-24 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231762
• 关键词: 22q11.2; Accounting; Affect; Biological; Birth; Candidate Disease Gene; Cardiac; Childhood; Chromosome abnormality; Clinical; Clinical Management; Cohort Studies; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Copy Number Polymorphism; Data; Defect; Development; Disease; Disease Association; Etiology; Family; Future; Genes; Genetic; Genetic Counseling; Genetic Variation; Genetic screening method; Genotype; Haplotypes; Hereditary Disease; Individual; Inherited; Instruction; Investigation; Live Birth; Modeling; Morbidity - disease rate; Mus; Outcome; Parents; Pathway interactions; Phenotype; Population; Prevalence; Prevention strategy; Principal Investigator; Public Health; Research Personnel; Risk; Single-Gene Defect; Testing; Therapeutic Intervention; Translating; Triad Acrylic Resin; United States National Institutes of Health; Variant; base; case control; cohort; density; design; disorder risk; expectation; genetic risk factor; genetic variant; genome wide association study; genome-wide; human disease; improved; insight; malformation; member; mortality; mouse model; novel; novel therapeutics; programs; research study

This program will use multiple approaches to identify the genetic basis of a significant subset of congenital heart defects called conotruncal and related heart defects (CTDs). We hypothesize and data suggest that a range of genetic mechanisms contribute to the etiology of these birth defects including SNPs, CNVs and rare variants, and that a multitude of approaches will help identify disease-related variants. To elucidate these mechanisms, in Aim 1 relatively unbiased genome wide analyses will be completed using a large, non- syndromic CTD cohort ascertained over the last 15 years. In particular an exact replication of our successful family-based discovery analyses will be performed, and inherited, de novo and maternal copy number variations (CNVs) that are associated with CTDs will be identified using a case-control design. Aim 2a will explore the hypothesis that the 22q11.2 deleted cohort, at-risk for CTDs, will unmask disease-related genes that also pertain to the larger population of non-deleted CTD cases. To test this hypothesis, genetic modifiers of the cardiac phenotype in the 22q11.2 deleted cohort (from Project 1) will be assessed for disease- association in the non-syndromic cohort (with matched CTDs) to replicate findings from the 22q11.2 deleted cohort and identify variants conferring disease risk in the CTD cohort. Aim 2b will translate discoveries made in mouse models (Project 3) deciphering the biological underpinnings of conotruncal development via the Tbx1 developmental pathway, into human disease. Genes and genetic pathways defined by the mouse experiments will be assessed for disease-relatedness in the non-syndromic CTD cohort. Finally, in Aim 3 large scale deep sequencing to identify rare and common genetic variants in disease-associated genes/loci identified from Aims 1 and 2 will be performed to identify the range of genetic mechanisms causing non- syndromic CTDs. The proposed studies leverage unique large syndromic and non-syndromic study cohorts to decipher the genetic basis of CTDs and apply both genome wide and candidate gene approaches. The family based model identifies both inherited and novel matemal genetic effects. Deep sequencing of associated and candidate loci will identify both rare and common disease-associated variants. RELEVANCE (See instructions): Congenital heart defects are the most common, serious birth malformation affecting approximately 1 in 200 live births. Despite their prevalence and public health implication, their etiology remains poorly understood. These studies will elucidate the genetic basis for a subset of these malformations so that novel therapeutic and preventive strategies can be designed, and clinical management and outcomes improved.

该计划将使用多种方法来确定先天性遗传病重要子集的遗传基础 心脏缺陷称为圆锥动脉干及相关心脏缺陷 (CTD)。我们假设并且数据表明 一系列遗传机制导致这些出生缺陷的病因，包括 SNP、CNV 和罕见的 变异，并且多种方法将有助于识别与疾病相关的变异。为了阐明这些 机制，在目标 1 中，相对公正的全基因组分析将使用大型、非 过去 15 年确定的综合征性 CTD 队列。特别是我们成功的精确复制 将进行基于家庭的发现分析，以及遗传、从头和母体拷贝数 将使用病例对照设计来识别与 CTD 相关的变异 (CNV)。目标 2a 将 探索这样的假设：22q11.2 删除的队列存在 CTD 风险，将揭示疾病相关基因 这也涉及大量未删除的 CTD 病例。为了检验这个假设，基因修饰剂 of the cardiac phenotype in the 22q11.2 deleted cohort (from Project 1) will be assessed for disease- 非综合征队列（具有匹配的 CTD）中的关联以复制删除的 22q11.2 的发现 队列并识别在 CTD 队列中赋予疾病风险的变异。目标 2b 将转化发现 在小鼠模型中制作（项目 3），通过破译圆锥干发育的生物学基础 Tbx1 发育途径导致人类疾病。小鼠定义的基因和遗传途径 实验将评估非综合征性 CTD 队列中的疾病相关性。最后，在目标 3 中 大规模深度测序，以识别疾病相关基因/位点中罕见和常见的遗传变异 将执行目标 1 和 2 中确定的遗传机制，以确定导致非 综合征性 CTD。拟议的研究利用了独特的大型综合征和非综合征研究队列 破译 CTD 的遗传基础并应用全基因组和候选基因方法。这 基于家庭的模型识别遗传和新的母体遗传效应。深度测序 相关基因座和候选基因座将识别罕见和常见疾病相关变异。 相关性（参见说明）： 先天性心脏缺陷是最常见、严重的出生畸形，影响大约二百分之一的人 活产数。尽管其普遍存在并具有公共卫生影响，但其病因仍知之甚少。 这些研究将阐明这些畸形的一部分的遗传基础，以便新的治疗方法 可以设计预防策略，并改善临床管理和结果。