Genotype and Clinical Outcome in Conotruncal Defects

圆锥动脉干缺陷是心脏流出道的畸形，占所有活产先天性心脏缺陷的16%。尽管医学和外科手术的进步，这一子集的先天性心脏缺陷是与显着的发病率和死亡率。在过去的十年中，该中心和研究人员已经确定了与这些疾病相关的多种遗传改变，包括2211个染色体缺失，以及JAG 1，NKX2.5和CFC 1基因的突变。尽管取得了这些进展，但先天性心脏病的病因学尚不完全清楚，基因型对临床结果的影响在很大程度上仍不清楚。我们 假设基因型部分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调查，以破译先天性先天性缺陷的遗传病因。我们进一步建议将我们的研究结果应用于基因型-表型分析，以调查遗传病因和临床结果之间的关系。具体而言，我们建议：（1）通过突变分析和基于家族的关联研究，检查NKX2.5及其发育伙伴对圆锥动脉干缺陷病因学的贡献，（2）检查 圆锥动脉干缺陷的受试者亚组是否与异位综合征有共同的遗传病因学，异位疾病基因的突变分析，和（3）研究圆锥动脉干缺陷受试者中遗传病因学和临床变异性/结果之间的关系。为了实现这最后一个目标;我们将在圆锥动脉干缺陷和已知基因型的受试者亚组中，通过回顾医疗记录， 直接对患者进行评估。我们将研究患有法洛四联症的受试者，这些受试者患有21三体、22 q11缺失、JAG 1突变或没有确定的综合征。我们将在动脉干或主动脉弓中断伴或不伴22 q11缺失的受试者中进行类似的二次研究。来自该项目和其他项目（项目2、4和5）的遗传发现将被纳入基因型/表型分析。该项目面向临床，将与多个项目（项目2、4和5）相互作用，并需要多个项目的实质性支持。 核心包括临床核心C、细胞培养和DNA分析核心D以及生物信息学和数据分析核心F。本项目的总体目标是研究遗传因素如何影响临床变异性，以便将来我们能够修改患者管理以改善临床结局。

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.