Mapping of a first locus for autosomal dominant myxomatous mitral-valve prolapse to chromosome 16p11.2-p12.1

Myxomatous mitral-valve prolapse (MMVP), also called Barlow disease, is a c ommon cardiac abnormality and affects up to 5% of the population. It is cha racterized by an excess of tissue that leads to billowing of the mitral lea flets, sometimes complicated by prolapse. Typical histological findings inc lude myxomatous degeneration and degradation of collagen and elastin. Previ ous reports have proposed an autosomal dominant inheritance of the trait, w ith age- and sex-dependent expression. By systematic echocardiographic scre ening of the first-degree relatives of 17 patients who underwent mitral-val ve repair, we have identified four pedigrees showing such an inheritance. G enomewide linkage analysis of the most informative pedigree (24 individuals , three generations) showed a significant linkage for markers mapping to ch romosome 16p, with a two-point maximum LOD score for D16S3068 (Z(max) = 3.3 0 at theta = 0). Linkage to D16S3068 was confirmed in a second family (Z(ma x) = 2.02 at theta = 0) but was excluded for the two remaining families, th us demonstrating the genetic heterogeneity of the disease. Multipoint linka ge analysis performed, with nine additional markers, on the two families wi th linkage gave maximum multipoint LOD scores of 5.45 and 5.68 for D16S3133 , according to a conservative and a stringent model, respectively. Haplotyp e analysis defined a 5-cM minimal MMVP-1 locus between D16S3068 (16p11.2) a nd D16S420 (16p12.1) and a 34-cM maximal interval between D16S404 and D16S3 068 when recombination events were taken into account only in affected indi viduals. The identification of this locus represents a first step toward a new molecular classification of mitral-valve prolapse.