Genetic Basis of Syndromic and Non-Syndromic Congential Heart Defects

描述（由申请人提供）：锥体缺陷（CTDs）占所有先天性心脏缺陷的36%，并且具有很高的发病率。虽然其病因尚不明确，但数据表明复杂的遗传机制有助于其病因。本程序将定义CTDs的遗传基础。CTDs遗传综合征的分子评价为其遗传基础提供了有价值的见解。特别是，对22q11.2缺失综合征的研究定义了一个大的CTD群体，确定了有助于心脏发育和疾病的基因（例如TBX1）和发育途径。为了继续这项工作，项目1将使用全基因组方法在一个特殊的22q11.2缺失患者队列中鉴定CTDs的遗传修饰因子。在项目2中，将完成一个独特的、大型非综合征性CTD患者队列的全基因组研究，以确定病例（遗传）和母体遗传效应。在一组患者中取得的发现将在另一组患者中检验其意义。基于22q11 DS的小鼠模型将用于阐明锥体形态发生的关键发育途径。在小鼠模型中描述的基因和发育途径将在两个患者队列中检查与疾病相关的遗传变异，项目1和项目2中的发现将依次在小鼠中检查表达模式和关键发育途径中的位置。这些研究中的候选基因将进行深度测序，以确定与疾病相关的全范围遗传变异。拟议的研究是高度互动的，利用独特的患者队列和小鼠模型，建立在长期合作的基础上，并验证以下假设：(1)22q11.2缺失队列将有助于揭示特发性心脏缺陷的遗传风险因素，(2)这些风险因素适用于非综合征性心脏队列，(3)关键发育途径可以在基因成员与人类疾病相关的小鼠中被阐明。这些研究将极大地扩展我们对CTDs遗传基础的认识，并将促进新的治疗和预防策略的发展。

DESCRIPTION (provided by applicant): Conotruncal defects (CTDs) comprise 36% of all congenital heart defects and carry significant morbidity. Although their etiology is poorly defined, data suggest that complex genetic mechanisms contribute to their etiology. This Program will define the genetic basis of CTDs. Molecular evaluation of genetic syndromes with CTDs have provided valuable insight into their genetic basis. In particular, studies on the 22q11.2 deletion syndrome defined a large CTD population, identified genes (e.g. TBX1) and developmental pathways contributing to cardiac development and disease. To continue this work, Project 1 will identify genetic modifiers of CTDs in an exceptional, large 22q11.2 deleted patient cohort using genome wide approaches. In Project 2, genome wide studies in a unique, large non-syndromic patient CTD cohort will be completed to identify both case (inherited) and maternal genetic effects. Discoveries made in one patient cohort will be examined for significance in the other. Mouse models based on 22q11 DS will be used to elucidate developmental pathways critical to conotruncal morphogenesis. Genes and developmental pathways described in the mouse models will be examined for disease associated genetic variants in each of the two patient cohorts, and discoveries in Projects 1 and 2 will in turn be examined in the mouse for expression pattern and placement in key developmental pathways. Candidate genes from these studies will be subject to deep sequencing to identify the full range of disease related genetic variants. The proposed studies are highly interactive, leverage unique patient cohorts and mouse models, build upon long standing collaborations, and test the hypotheses that: (1) the 22q11.2 deleted cohort will serve to unmask genetic risk factors for the characteristic cardiac defects, (2) these risk factors apply to the non-syndromic cardiac cohort, and (3) critical developmental pathways can be elucidated in the mouse whose gene members are disease- related in humans. These studies wilt greatly expand our understanding of the genetic basis of CTDs, and will promote the development of novel therapeutic and preventive strategies.