AUTOSOMAL-DOMINANT SUPRAVALVULAR AORTIC-STENOSIS - LOCALIZATION TO CHROMOSOME-7

Supravalvular aortic stenosis (SVAS) is a localized or diff use congen ital narrowing of the ascending aorta which may occur sporadically, as a familial defect, or in association with Williams syndrome. Familial cases suggest an autosomal dominant gene defect but the underlying mo lecular basis of SVAS is unknown. In this study, we sought to localize the genetic defect in familial SVAS by linkage analysis in a large th ree generation family. A total of 44 polymorphic markers were examined for linkage, including 17 Southern blot-based RFLPs, 2 PCR-based RFLP s, and 25 microsatellites, primarily of the (CA)n repeat type. We repo rt linkage of the disease phenotype to a highly informative (CA)n repe at marker, Mfd 50, at locus D7S440 which has been localized to chromos ome arm 7q. Using a 100% penetrance model, which was more conservative than lower values of penetrance, a peak LOD score of 4.66 at a recomb ination frequency of 0.043 was found. A number of candidate genes have been localized to this region, including collagen 1A2, laminin B1, an d elastin. Based on our preliminary linkage data, the abnormal microsc opic appearance of aortic elastic fibers in SVAS, and analogous animal and human diseases associated with elastic fiber and vascular abnorma lities, there is indirect evidence suggesting elastin as a possible ca ndidate gene for this disorder.