GENETIC ANALYSIS OF INHERITED CONGENITAL HEART DISEASES

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(Adapted from the Applicant's Abstract) Congenital heart defects are common human malformations that cause significant morbidity, mortality, in addition to substantial social and economic costs. Birth defect registries indicated congenital heart defects occur in approximately 1 percent of human lie births and 10 percent of stillbirths (1). Over the past 30 years major advances have occurred in the diagnosis and management of heart defects in infants and children. Far less is known about the normal molecular signals or pathways that direct human cardiac morphogenesis, nor how and why these processes sometimes fail. Application of human genetic analysis to the study of inherited congenital heart disease has enormous potential to provide novel insights into these complex human processes. The focus of this application is to define the molecular causes of inherited human congenital heart defects. The investigators have recently identified three loci that cause human cardiac malformations. (1) Holt-Oram syndrome which maps tot chromosome 12q2 is caused by mutations in human TBX5. This congenital malformation causes skeletal and ventricular septal defects and sinus or atrio- ventricular septal defects, and sinus or atrio-ventricular nodal abnormalities that arise independent of septation defects). (2) The investigators have recently mapped gene defects that cause non-syndromic secundum atrial septal defects with associated atrioventricular conduction delays to chromosome 5q and have demonstrated the causal gene at this locus to be Nkappax2.5 (also termed hCSx). (3) The investigators have defined a locus on chromosome 5p that causes non-syndromic secundum atrial septal defects without conduction defects. Individuals affected by mutations in the 5q and 5p loci may have normal cardiac structure, atrial septal aneurysm, bicuspid aortic valve, persistent left superior vena cava, or more complex structural defects (such as tetralogy of Fallot). This variable expressivity combined with reduced penetrance of these gene mutations have partially obscured the familial (and genetic) nature of these congenital heart defects. The investigators' data and studies by others clearly demonstrate genetic heterogeneity of human congenital heart disease. Further identification and characterization of mutations in known disease genes and those yet to be defined should therefore provide a better understanding of human cardiac morphogenesis and the molecular basis of cardiac malformations. Development and characterization of animal models with these mutations should help explain the variable expression of these mutations. Ultimately these studies may also improve the understanding of non-familial congenital heart disease. The investigators propose to address these issues through the following specific aims: (1) characterize further the clinical manifestations of human TBX5 and Nkappax2.5 mutations to elucidate structure/function relationships; (2) identify other gene defects that cause heritable cardiac malformations using positional cloning and candidate gene analyses; (3) engineer and characterize mice with human TBX5 mutations in other cardiac malformation genes; and (5) test the hypothesis that TBX5 is subject to allelic exclusion in some cells.