Copy Number Variants for Discovery of Congenital Heart Genes

描述（由申请人提供）： 大量证据表明先天性心脏病（CHD）的遗传贡献，但负责大多数CHD的特定基因仍然未知。以前确定的CHD突变已在基于家庭的调查中发现。然而，大多数CHD是作为一种意外和无法解释的事件出现的，可能是由于某些基因变异的不完全突变和与其他基因相关的生殖适应性受损。这对于严重的CHD尤其如此，如果不治疗，会导致早期死亡。在本申请中，我们建议关注散发性而不是家族性CHD。受试者将患有重度CHD，定义为紫绀病变和其他通常需要在婴儿期进行干预的病变。基于关键发育基因的异常剂量导致某些CHD的证据，我们将对受影响儿童和未受影响父母的三人组中的从头拷贝数变异进行全基因组分析。我们还将通过病例对照全基因组关联研究评估导致严重CHD的等位基因。我们将确定体细胞突变是否会导致一些散发性的严重CHD，并将分析人类畸形心脏的基因转录。我们的研究将共同评估以前定义的CHD基因的贡献，确定新的位点，基因，突变和机制，并评估基因型-表型关系。我们的研究利用现代基因组方法，并将使用新的测序和转录分析策略。我们预计这些研究将促进与该联盟其他研究中心的高效合作，并将为心脏发展联盟提供有关人类心脏发生的基础知识。我们提出了四个具体目标：1。使用亚基因组捕获策略来询问已知和候选CHD基因以及新鉴定的CHD基因的序列和拷贝数，并评估基因型-表型相关性。2.确定体细胞突变是否导致或调节CHD。3.定义新的严重CHD位点（通过发现从头拷贝数变异和全基因组关联研究），基因和突变。4.定义RNA表达在畸形人类心脏的受影响区域。三个核心将支持这些研究：复杂CHD表型的成像核心，基因组分析核心和序列分析核心。相关性（参见说明）：我们的研究将确定导致严重CHD的新基因和突变，使基因型-表型研究成为可能，为研究遗传因素与长期结局的关系提供框架，并提供复发风险的数据。来自拟议研究的数据，以及我们的教师，临床和遗传学资源，将推进NHLBI儿科心血管翻译联盟的目标。

DESCRIPTION (provided by applicant): Abundant evidence indicates a genetic contribution to congenital heart disease (CHD), but the specific genes responsible for most CHD are still unknown. Previously identified CHD mutations have been found in family-based investigations. However, most CHD arises as an unexpected and unexplained event, likely due to incomplete penetrance of some gene variants and impaired reproductive fitness associated with others. This is particularly true for severe CHD which, if untreated, causes early lethality. In this application, we propose to focus on sporadic rather than familial CHD. Subjects will have severe CHD defined as cyanotic lesions and others that usually require intervention in infancy. Based on evidence that abnormal dosage of critical developmental genes causes some CHD, we will conduct genome-wide analyses for de novo copy number variants in trios of the affected child and unaffected parents. We will also assess alleles that contribute to severe CHD through case-control whole genome association studies. We will determine whether somatic mutations account for some sporadic, severe CHD and will analyze gene transcription in human malformed hearts. Together our studies will assess the contribution of previously defined CHD genes, identify new loci, genes, mutations and mechanisms, and evaluate genotype-phenotype relationships. Our studies harness modern genomic approaches and will use novel sequencing and transcription profiling strategies. We anticipate these investigations will foster highly productive collaborations with other research centers in this Consortium and will contribute fundamental knowledge about human cardiogenesis to the Cardiac Development Consortium. We propose four specific aims: 1. Use subgenome capture strategies to interrogate the sequence and copy number of known and candidate CHD genes, as well as newly identified CHD genes, and assess genotype-phenotype correlations. 2. Determine if somatic mutations cause or modulate CHD. 3. Define novel severe CHD loci (by discovery of de novo copy number variants and by genome-wide association studies), genes, and mutations. 4. Define RNA expression in affected regions of malformed human hearts. Three cores will support these studies: an Imaging Core for Complex CHD Phenotyping, a Genomic Analyses Core, and a Sequence Analysis Core. RELEVANCE (See instructions): Our studies will define new genes and mutations that cause severe CHD, enable genotype-phenotype studies, provide a framework to study the relationship of genetic factors to long-term outcomes, and provide data on recurrence risks. Data from the proposed studies, as well as our faculty, clinical and genetics resources, will advance the goals of the NHLBl's Pediatric Cardiovascular Translation Consortium.