The Genetic Etiology of Conotruncal Cardiac Defects

描述（由申请人提供）：圆锥动脉干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%。尽管其临床意义，其病因是知之甚少。研究表明，圆锥动脉干缺陷的病因是异质性和复杂的，包括环境和遗传因素。由于多重家庭服从参数连锁分析是非常罕见的，替代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经通过遗传综合征的分子分析和动物模型确定。流行病学研究还表明，叶酸代谢途径可能会影响圆锥动脉干缺陷的风险。我们已经确定了一个大的圆锥动脉干心脏缺陷的受试者队列，并确定了两个关键发育基因NKX2.5和CFCI的患者亚组的突变。基于文献和我们的初步研究，我们假设三个特定的代谢和发育途径有助于圆锥动脉干缺陷的病因学，包括：（1）叶酸-同型半胱氨酸代谢轴，（2）NKX2.5及其分子伴侣，（3）与左右不对称异常相关的人类疾病基因（如CFC 1）。我们建议继续我们的努力，以确定圆锥动脉干缺陷的遗传基础，使用基于家庭的关联研究和这些途径中的候选基因的突变分析。对于叶酸-同型半胱氨酸代谢轴的遗传变异，新的基于家族的关联研究将检查母体或胚胎基因型是否影响圆锥动脉干缺陷的风险。这些研究也将开始探讨母胎基因型相互作用、作用于母体或胚胎水平的基因-基因相互作用以及基因-环境相互作用是否影响圆锥动脉干发育。将研究发育基因，如与NKX2.5相互作用的基因或参与左右不对称的基因的突变，并在选定的情况下，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动脉干缺陷的遗传因素。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.