Beginning in 1990, the molecular genetic epidemiology of endocardial cushion defects in four groups of individuals was investigated in this subproject within a SCOR in Pediatric Cardiovascular Disease. Subjects included those with Down syndrome and endocardial cushion defects, those with non-syndromic endocardial cushion defects, those with Down syndrome and no congenital heart disease, and those with normal hearts. Examinations were carried out in the relatives of these subjects to ascertain whether they had endocardial cushion defects and other chromosome 21-related disorders, such as Down syndrome and Alzheimer's disease. This was accomplished by obtaining family pedigrees and examining 1st, 2nd and 3rd degree relatives utilizing electrocardiographic and echocardiographic techniques. Venous blood was obtained from the probands and the relatives for association studies with DNA probes that were known to relate to chromosome 21 and to genes located on other chromosomes that may affect cardiac embryogenesis. Segregation analysis focused on families of the subjects with non-syndromic endocardial cushion defects to determine whether there was evidence for a major gene defect which resulted in deformities of the atrioventricular canal. If and when such evidence was found, linkage studies were carried out in an attempt to pinpoint the location of the major gene in the genome.