The Genetic Etiology of Conotruncal Cardiac Defects

描述（申请人提供）：圆锥状心脏缺陷是心脏流出道的畸形，占所有先天性心脏缺陷的16%。尽管它们具有临床意义，但其病因尚不清楚。研究表明，锥体缺陷的病因是复杂的，包括环境和遗传因素。由于符合参数连锁分析的多重家族非常罕见，因此已经采取了其他方法来确定这些心脏缺陷的遗传原因。候选基因和染色体位点已通过遗传综合征和动物模型的分子分析确定。流行病学研究也表明，叶酸代谢途径可能影响发生锥体缺陷的风险。我们已经确定了一个大队列的conotruncal心脏缺陷的受试者，并已经确定了两个关键发育基因NKX2.5和CFCI的一个亚组患者突变。基于文献和我们的初步研究，我们假设三种特定的代谢和发育途径有助于圆锥锥体缺陷的病因学，包括：(1)叶酸-同型半胱氨酸代谢轴，(2)NKX2.5及其分子伙伴，以及(3)与左右不对称异常相关的人类疾病基因（如CFC1）。我们建议继续努力，利用基于家族的关联研究和候选基因的突变分析来确定锥体缺陷的遗传基础。对于叶酸-同型半胱氨酸代谢轴的遗传变异，新的基于家庭的关联研究将检查母体或胚胎基因型是否会影响圆锥锥体缺陷的风险。这些研究还将开始探索母体-胎儿基因型相互作用、在母体或胚胎水平上的基因-基因相互作用以及基因-环境相互作用是否影响圆锥发育。将研究发育基因，例如与NKX2.5相互作用的基因或参与左右不对称的基因，以研究突变，并在某些情况下研究胚胎基因型对疾病的影响。该项目的总体目标是进一步阐明导致圆锥锥体缺陷病因的遗传因素。有了这些数据，可以评估基因型对临床结果的影响，并为未来设计改进的管理策略。

DESCRIPTION (provided by applicant): Conotruncal cardiac defects are malformations of the outflow tracts of the heart, which account for 16% of all congenital heart defects. Despite their clinical significance, their etiology is poorly understood. Studies indicate that the etiology of conotruncal defects is heterogeneous and complex, and includes both environmental and genetic factors. Because multiplex families amenable to parametric linkage analyses are extraordinarily rare, alternative approaches to identify genetic causes of these heart defects have been taken. Candidate genes and chromosomal loci have been identified through molecular analyses of genetic syndromes and from animal models. Epidemiologic studies have also suggested that the folate metabolic pathway may influence the risk of developing conotruncal defects. We have ascertained a large cohort of subjects with conotruncal cardiac defects and have identified mutations in a subset of patients in two key developmental genes: NKX2.5 and CFCI. Based on the literature and our preliminary studies, we hypothesize that three specific metabolic and developmental pathways contribute to the etiology of conotruncal defects including: (1) the folate-homocysteine metabolic axis, (2) NKX2.5 and its molecular partners, and (3) human disease genes (such as CFC1) associated with the abnormalities of left-right asymmetry. We propose to continue our efforts to define the genetic basis of conotruncal defects using family-based association studies and mutation analyses of candidate genes in these pathways. For genetic variants in the folate-homocysteine metabolic axis, novel family-based association studies will examine whether the maternal or embryonic genotype influences the risk of conotruncal defects. These studies will also begin to explore whether maternal-fetal genotype interactions, gene-gene interactions acting at the level of the mother or embryo, and gene-environment interactions influence conotruncal development. Developmental genes, such as those interacting with NKX2.5 or those participating in left-right asymmetry, will be studied for mutations and in select cases, for the influence of embryonic genotype on disease. The overall goal of this project is to further elucidate genetic factors that contribute to the etiology of conotruncal defects. With this data, the impact of genotype on clinical outcome can be assessed and improved management strategies devised for the future.