The Genetic Basis of Conotruncal Defects

描述(由申请人提供)： 尽管在医学和外科方面取得了显著的进步，但先天性心脏病(CHD)仍然与严重的发病率和早期死亡率有关，并成为一个重大的公共卫生问题。然而，对冠心病的病因了解甚少，因此从发病机制出发的预防策略和治疗方法也很少。有证据表明，遗传因素和环境因素都参与了冠心病的病因，而且越来越明显的是，冠心病是复杂的遗传特征，疾病的风险由多个遗传因素的组合决定。研究表明，遗传因素也会影响临床结果。随着技术和方法的快速进步，现在有可能进行大规模的基因组分析，以确定以复杂特征为特征的常见疾病的遗传风险因素，但需要大量的研究队列。儿科心脏基因组学联盟的成立有望克服这最后一个障碍。这项应用建议在一大群相关的冠心病中进行全基因组研究，即圆锥干缺陷，以确定疾病的遗传风险因素。遗传变异(单核苷酸多态和拷贝数变异)与疾病风险的关联将在发现队列中进行测试，并在复制队列中精确复制发现。还将进行系统分析，以发现与疾病相关的途径。与先前存在的样本相结合，该联盟确定的病例将允许进行由具体诊断确定的全队列和分组分析。分析之后将对相关基因、CNV和途径成员进行深度测序，以确定特定的与疾病相关的基因变化。最后，将对法乐氏四联症患者的亚组病例进行分析，探讨基因与临床结局之间的关系。建议的研究提供了一种相对公正的方法来确定这一大组冠心病的新的遗传危险因素。结合发育生物学联盟的发现，这些研究将确定新的疾病机制，并开始推进预防和治疗冠心病及相关疾病的机会。相关性(见说明)：先天性心脏缺陷(CHD)是最常见、最主要的出生缺陷，继续与重大的终生发病率和早期死亡率有关。这些研究将开始确定CHD的一个大亚组的遗传因素，这些亚组的病因在其他方面了解得很少。这些发现将提供对疾病机制的洞察，并允许采取更具战略性的预防和治疗卫生措施。

DESCRIPTION (provided by applicant): Despite remarkable medical and surgical advances, congenital heart defects (CHD) continue to be associated with significant morbidity and early mortality and present a substantial public health concern. However, the etiology of CHD is poorly understood and thus preventive strategies and therapies based on mechanism of disease are few. Evidence suggests that both genetic and environmental factors contribute to the etiology of CHD and it is increasingly apparent that CHD are complex genetic traits where the risk of disease is determined by the combination of multiple genetic factors. Research suggests that genetic factors influence clinical outcome as well. With rapid technological and methodological advances, large scale genomic analyses to identify genetic risk factors in common diseases characterized as complex traits are now possible but require large study cohorts. The establishment of the Pediatric Cardiac Genomics Consortium promises to overcome this last hurdle. This application proposes to perform genome wide studies in a large, related group of CHD, namely conotruncal defects, to identify genetic risk factors for disease. The association of genetic variants (single nucleotide polymorphisms and copy number variants) with the risk of disease will be tested in a discovery cohort, and findings replicated exactly in a replication cohort. Systems analyses to discover disease related pathways will also be performed. In conjunction with pre-existing samples, cases ascertained by the Consortium will allow for full-cohort and subgroup analyses defined by specific diagnoses. Analyses will be followed by deep sequencing of associated genes, CNVs and members of pathways to identify specific disease-related genetic alterations. Finally, analyses exploring the association of genotype with clinical outcome in the subset of cases with tetralogy of Fallot will be performed. The proposed studies provide a relatively unbiased approach to identify novel genetic risk factors for this large group of CHD. In conjunction with discoveries from the Developmental Biology Consortium, these studies will identify novel mechanisms of disease and begin to advance opportunities for the prevention and therapy of CHD and associated morbidities. RELEVANCE (See instructions): Congenital heart defects (CHD) are the most common, major birth defect and continue to be associated with significant life-long morbidities and early mortality. These studies will begin to identify genetic factors for a large subset of CHD whose etiology is otherwise poorly understood. Such discoveries will provide insight into the mechanisms of disease and allow for more strategic preventive and therapeutic health measures.