Secundum atrial septal defect (ASD) is a common congenital heart defect accounting for 10% of isolated congenital heart disease. Some individuals with ASD have a family history of this defect; some familial ASD kindreds also have other congenital heart defects and co-existing atrioventricular (AV) conduction abnormalities. The genetic basis for these observations remains unclear. Preliminary studies on seven kindreds in whom ASD was transmitted as an autosomal dominant trait confirmed these observations and also identified loci on chromosome 5p and 5q through genetic linkage analysis. In a kindred mapping to the 59 locus, the clinical status of all family members can be accounted for by a model of incomplete penetrance and variable expressivity. In three kindreds mapping to the 5q locus, there is full disease penetrance, variable expressivity. In three kindreds mapping to the 5q locus, there is full disease penetrance, variable expressivity and affected individuals have associated AV conduction abnormalities. Thus, familial ASD is genetically heterogeneous; reduced disease penetrance and variable expressivity occur in some kindreds. A genome-wide search for a third locus is underway in one kindred, and three other kindreds are being clinically evaluated. The following studies are proposed: 1. To identify additional kindreds in whom ASD appears to be inherited as an autosomal dominant trait and map the kindreds to known loci on chromosome 5p and 5q. 2. To refine the genetic map of the chromosome 5p and 5q loci, construct a physical map, identify candidate genes and screen them for mutations. 3. To perform a genome-wide search to identify additional for familial ASD in kindreds that do not map to chromosome 5q or 5p. 4. To make a mouse model of familial ASD. These specific aims have been developed based upon the rationale and feasibility demonstrated in preliminary data. The availability of multiple kindreds at different stages of genetic evaluation is key to ensuring successful completion of the proposed studies. Based on preliminary studies, at least three genes can cause ASD. To date there have been no report of a gene whose mutation causes a simple, common heart defect such as ASD. Identification of such genes would provide an important perspective of both normal and abnormal cardiac development.