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)与基因有关，但导致大多数CHD的特定基因仍不清楚。在以家庭为基础的调查中发现了以前发现的CHD突变。然而，大多数CHD的发生是意想不到的和无法解释的事件，可能是由于某些基因变异的不完全外显和与其他基因变异相关的生殖适合性受损。对于严重的CHD来说尤其如此，如果不治疗，会导致早期死亡。在这一应用中，我们建议关注散发性而不是家族性冠心病。受试者将患有严重的CHD，定义为紫绿色皮损和其他通常需要在婴儿时期进行干预的疾病。基于关键发育基因的异常剂量会导致一些CHD的证据，我们将对患病儿童和未患病父母的三人组进行全基因组拷贝数变异分析。我们还将通过病例对照全基因组关联研究来评估导致严重冠心病的等位基因。我们将确定体细胞突变是否导致一些零星的、严重的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先前定义的CHD基因的贡献，识别新的基因座、基因、突变和机制，并评估基因型-表型关系。我们的研究利用了现代基因组方法，并将使用新的测序和转录图谱策略。我们预计这些研究将促进与该联盟中其他研究中心的高成效合作，并将为心脏发展联盟贡献有关人类心脏发生的基础知识。我们提出了四个具体的目标：1.使用亚基因组捕获策略来查询已知和候选的CHD基因以及新发现的CHD基因的序列和拷贝数，并评估基因与表型的相关性。2.确定体细胞突变是导致还是调节CHD。3.定义新的严重冠心病基因座(通过发现新的拷贝数变异和全基因组关联研究)、基因和突变。4.确定畸形心脏受影响区域的RNA表达。三个核心将支持这些研究：一个用于复杂CHD表型的成像核心，一个基因组分析核心，和一个序列分析核心。相关性(参见说明)：我们的研究将定义导致严重冠心病的新基因和突变，使基因-表型研究成为可能，提供一个框架来研究遗传因素与长期结果的关系，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，将推动NHLB1的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.