Genotype and Clinical Outcome in Conotruncal Defects

圆锥干畸形是热量流出道的畸形，占活产先天性心脏病的16%。尽管医学和外科技术取得了进步，但这类先天心脏缺陷仍与显著的发病率和死亡率有关。在过去的十年里，该中心和研究人员已经发现了与这些疾病相关的多种基因改变，包括2211条染色体缺失，以及JAG1、NKX2.5和CFC1基因的突变。尽管取得了这些进展，但牙列缺陷的病因还不完全清楚，而且基因对临床结果的影响在很大程度上仍不清楚。我们 假设基因在一定程度上可以预测临床变异性和结果。为了验证这一假设，我们建议继续我们的研究，以破译ConotmncaI缺陷的遗传病因学。我们进一步建议将我们的发现应用于基因-表型分析，以调查遗传病因和临床结果之间的关系。具体地说，我们建议：(1)通过突变分析和基于家系的关联研究来检验NKX2.5及其发育伙伴在圆锥干畸形病因中的贡献；(2)检验 研究圆锥干缺陷症患者是否有共同的遗传病因学，以及(3)研究圆锥干缺陷症患者的遗传病因学与临床变异/预后的关系。为了实现这最后一个目标，我们将通过回顾病历和已知的基因，来研究基因与心脏解剖、围手术期病程和心血管中间结局之间的关系。 直接对病人进行评估。我们将研究患有法洛四联症的受试者，这些受试者有21三体、22q11缺失、JAG1突变或未发现综合征。我们将在有或没有22q11缺失的动脉干或主动脉弓中断的受试者中进行类似的二次研究。该项目和其他项目(项目2、项目4和项目5)的基因发现将被纳入基因/表型分析。该项目面向临床，将与多个项目(项目2、4和5)互动，并将需要来自几个项目的底层支持 核心包括临床核心C、细胞培养和DNA分析核心D和生物信息学和数据分析核心F。这项研究的总体目标是检查遗传因素如何影响临床变异性，以便在未来，我们可以改进患者管理，以改善临床结果。

Conotruncal defects are malformations of the outflow tracts of the heat which account for 16% of all congenital heart defects in livebirths. Despite medical and surgical advances, this subset of congenital heart defects is associated with significant morbidity and mortality. Over the past decade, this center and investigator have identified multiple genetic alterations associated with these disorders incIuding 2211 chromosomal deletions, and mutations in the JAG1, NKX2.5 and CFC1 genes. Despite these advances, the etiology of conotmncal defects is incompletely understood, and the impact of genotype on clinical outcome remains largely unknown. We hypothesize that genotype in part predicts clinical variability and outcome. To test this hypothesis, we propose to continue our investigations to decipher the genetic etiology of conotmncaI defects. We further propose to apply our findings to genotype-phenotype analyses that investigate the relationship between genetic etiology and clinical outcome. Specifically, we propose to: (1) examine the contribution of NKX2.5 and its developmental partners to the etiology of conotruncal defects by mutation analysis and family-based association studies, (2) examine whether a subset of subjects with conotruncal defects share a common genetic etiology with heterotaxy syndrome mutation analysis of heterotaxy disease-genes, and (3) investigate the relationship between genetic etiology and clinical variability/outcome in subjects with conotruncal defects. To accomplish this last aim; we will examine the relationship between genotype and cardiac anatomy, peri-operative course and intermediate cardiovascular outcome in a subset of subjects with conotruncal defects and a known genotype by review of medical records and direct patient evaluation. We will study subjects with tetralogy of Fallot who have trisomy 21, a 22q11 deletion, a JAG1 mutation or no identified syndrome. We will perform similar, secondary studies in subjects with truncus arteriosus or interrupted aortic arch with or without a 22q11 deletion. Genetic discoveries from this and other projects (Projects 2, 4, and 5) will be incorporated into the genotype/phenotype analyses. This project is clinically oriented, will interact with several prqiects (Projects 2, 4, and 5) and will require substandaI support from several Cores including the Clinical Core C, the Cell Culture and DNA Analysis Core D, and the Bioinformatics and Data Analysis Core F. The overall goal of this prqiect is to examine how genetic factors contribute to clinical variability so that, in the future, we can modify patient management to improve upon clinical outcome.