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

该计划将使用多种方法来确定一个显着的先天性心脏病子集的遗传基础。 心脏缺陷称为圆锥动脉干和相关的心脏缺陷（CTD）。我们假设和数据表明， 一系列遗传机制有助于这些出生缺陷的病因学，包括SNP、CNV和罕见的 变异，以及多种方法将有助于识别疾病相关的变异。阐明这些 机制，在目标1中，相对无偏的全基因组分析将使用大的，非 过去15年确定的综合征CTD队列。特别是一个精确复制我们成功的 将进行基于家族的发现分析，并对遗传、从头和母体拷贝数进行分析。 将使用病例对照设计鉴定与CTD相关的CNV。目标2a将 探索22q11.2缺失队列（有CTD风险）将揭示疾病相关基因的假设 这也适用于非删除CTD病例的较大人群。为了验证这一假设，遗传修饰剂 将评估22q11.2缺失队列（来自项目1）中心脏表型的疾病- 在非综合征队列（具有匹配的CTD）中与22q11.2缺失的重复结果的关联 在CTD组群中确定赋予疾病风险的变异。目标2b将转化发现 在小鼠模型（项目3）解密锥干发育的生物学基础， Tbx 1发育途径与人类疾病的关系。小鼠定义的基因和遗传途径 在非综合征性CTD组群中评估实验的疾病相关性。最后，在Aim 3中 大规模深度测序，以识别疾病相关基因/位点中的罕见和常见遗传变异 目的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。的 基于家族的模型识别了遗传和新的母体遗传效应。的深度测序 相关和候选基因座将鉴定罕见和常见疾病相关变体。 相关性（参见说明）： 先天性心脏缺陷是最常见的，严重的出生畸形影响约1/200 活产尽管其流行和公共卫生的影响，其病因仍然知之甚少。 这些研究将阐明这些畸形的一个子集的遗传基础， 可以设计预防策略，改善临床管理和结果。

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.