SUSCEPTIBLE GENES FOR CONOTRUNCAL CARDIAC DEFECTS

心脏圆锥体缺陷的易感基因

• 批准号: 6565107
• 负责人: Deborah A Driscoll
• 金额: $ 18.67万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565107
• 关键词: clinical research; congenital heart disorder; cytogenetics; developmental genetics; gene deletion mutation; gene mutation; genetic screening; genetic susceptibility; human subject; linkage disequilibriums; phenotype; point mutation; polymerase chain reaction; single strand conformation polymorphism

(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.

（摘自申请人摘要）锥体状心脏缺陷（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。本实验室证实CTCD的病因之一是染色体22q11.2区域的单倍不全。最近的动物研究表明，锥体发育涉及多个基因。基于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中发现了几个可能在心脏发育中起作用的基因。因此，该项目的主要目标是确定最近鉴定的22和其他染色体位点上的哪些基因有助于圆锥锥体畸形的发展。研究者建议使用一些新的方法，包括非参数连锁分析（传播不平衡检验）和种群关联研究来实现这一目标。基于CTCD与22q11缺失的显著相关性，研究者提出一些未缺失的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，研究人员还将在未删除的CTCD患者中筛选这些基因的突变。此外，研究人员提出，缺失CTCD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。在22q11缺失的个体中，心脏表型的潜在遗传修饰因子将使用群体关联或传统的病例对照研究设计进行评估。这些因素也可能作为未缺失CTCD患者的心脏易感位点。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，这使他们成为少数能够进行拟议研究的中心之一。