SUSCEPTIBLE GENES FOR CONOTRUNCAL CARDIAC DEFECTS

圆锥动脉干心脏缺陷（CTCD）约占先天性心脏缺陷的17%。 然而，在大多数CTCD患者中，尚未确定具体原因。本实验室证明CTCD的病因之一是染色体22q11.2区域的单倍不足。 最近的动物研究表明，有多个基因参与圆锥干的发展。根据其在心脏中的表达模式以及对流出道和主动脉弓异常的小鼠模型和转基因小鼠的观察，已经确定了几个优秀的CTCD候选基因。此外，在22q11.2内已经确定了几个基因，这些基因可能在心脏发育中发挥作用。 因此，该项目的主要目标是确定最近在22和其他染色体位点上鉴定的基因中哪些有助于圆锥动脉干畸形的发展。研究者建议使用几种新的方法，包括非参数连锁分析（传递不平衡检验）和群体关联研究来实现这一目标。 基于CTCD与22q11缺失的显著相关性，研究者提出一些非缺失型CTCD患者可能在22q11.2内的候选基因中存在点突变或较小的缺失。 因此，研究人员还将在非缺失型CTCD患者中筛查这些基因的突变。此外，研究人员提出，CTCD缺失患者心脏病变的存在和严重程度可能是遗传背景差异的结果。 将使用人群关联或传统病例对照研究设计评价22q11缺失个体中心脏表型的潜在遗传修饰因子。 这些因素也可能作为非缺失型CTCD患者的心脏易感基因座。通过核心A和B的努力，研究人员拥有大量资源，包括来自400多名CTCD患者的DNA样本库，这使他们成为少数能够进行拟议研究的中心之一。

(Adapted from the Applicant's Abstract) Conotruncal cardiac defects (CTCD) account for approximately 17 percent of congenital heart defects. However, in the majority of patients with CTCD a specific cause has not been identified. This laboratory demonstrated that one of the etiologies of CTCD is haploinsufficiency for chromosomal region 22q11.2. Recent animal studies suggest that there are multiple genes involved in conotruncal development. Several excellent candidate genes for CTCD have been identified based on their expression pattern in the heart and the observation of mouse models and transgenic mice with abnormalities of the outflow tracts and aortic arches. In addition, several genes have been identified within 22q11.2 which may play a role in cardiac development. Hence, the major goal of this project is to determine which of the recently identified genes on 22 and on other chromosomal loci contribute to the development of conotruncal malformations. The investigators propose to use several novel approaches including non-parametric linkage analysis (transmission disequilibrium test) and population association studies to accomplish this goal. Based on the significant association of CTCD with deletions of 22q11, the investigators propose that some non-deleted CTCD patients may have point mutations or smaller deletions in candidate genes within 22q11.2. Therefore, the investigators will also screen for mutations in these genes in non-deleted CTCD patients. Furthermore, the investigators propose that the presence and severity of the cardiac lesion in deleted CTCD patients may result from differences in genetic background. Potential genetic modifiers of the cardiac phenotype in individuals with 22q11 deletions will be evaluated using a population association, or traditional case-control study design. These factors may also act as cardiac susceptibility loci in non-deleted CTCD patients. Through the efforts of Core A and B the investigators have significant resources including banked DNA samples from over 400 CTCD patients which make them one of the few centers capable of performing the proposed studies.