REDUCED PENETRANCE, VARIABLE EXPRESSIVITY, AND GENETIC-HETEROGENEITY OF FAMILIAL ATRIAL SEPTAL-DEFECTS

Background-Secundum atrial septal defect (ASD) is a common congenital heart malformation that occurs as an isolated anomaly in 10% of indivi duals with congenital heart disease. Although some embryological pathw ays have been elucidated, the molecular etiologies of ASD are not full y understood. Most cases of ASD are isolated, but some individuals wit h ASD have a family history of this defect or other congenital heart m alformations. Methods and Results-Clinical evaluation of three familie s identified individuals with ASD in multiple generations. ASD was tra nsmitted as an autosomal dominant trait in each family. ASD was the mo st common anomaly, but other heart defects occurred alone or in associ ation with ASD in individuals from each kindred, Genome-wide linkage s tudies in one kindred localized a familial ASD disease gene to chromos ome 5p (multipoint LOD score=3.6, theta=0.0). Assessment of 20 family members with the disease haplotype revealed that 9 had ASD, 8 were cli nically unaffected, and 3 had other cardiac defects (aortic stenosis, atrial septal aneurysm, and persistent left superior vena cava). Famil ial ASD did not map to chromosome 5p in two other families. Conclusion s-Familial ASD is a genetically heterogeneous disorder; one disease ge ne maps to chromosome 5p. Recognition of the heritable basis of famili al ASD is complicated by low disease penetrance and variable expressiv ity. Identification of ASD or other congenital heart defects in more t han one family member should prompt clinical evaluation of all relativ es.