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.
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