Mapping of a First Locus for Autosomal Dominant Myxomatous Mitral-Valve Prolapse to Chromosome 16p11.2-p12.1

Abstract

Myxomatous mitral-valve prolapse (MMVP), also called Barlow disease, is a common cardiac abnormality and affects up to 5% of the population. It is characterized by an excess of tissue that leads to billowing of the mitral leaflets, sometimes complicated by prolapse. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Previous reports have proposed an autosomal dominant inheritance of the trait, with age- and sex-dependent expression. By systematic echocardiographic screening of the first-degree relatives of 17 patients who underwent mitral-valve repair, we have identified four pedigrees showing such an inheritance. Genomewide linkage analysis of the most informative pedigree (24 individuals, three generations) showed a significant linkage for markers mapping to chromosome 16p, with a two-point maximum LOD score for D16S3068 (Zmax=3.30 at straight theta=0). Linkage to D16S3068 was confirmed in a second family (Zmax=2.02 at straight theta=0) but was excluded for the two remaining families, thus demonstrating the genetic heterogeneity of the disease. Multipoint linkage analysis performed, with nine additional markers, on the two families with linkage gave maximum multipoint LOD scores of 5.45 and 5.68 for D16S3133, according to a conservative and a stringent model, respectively. Haplotype analysis defined a 5-cM minimal MMVP-1 locus between D16S3068 (16p11.2) and D16S420 (16p12. 1) and a 34-cM maximal interval between D16S404 and D16S3068 when recombination events were taken into account only in affected individuals. The identification of this locus represents a first step toward a new molecular classification of mitral-valve prolapse.

Lack of Association Between Perlecan Gene Intron 6 BamHI Polymorphism and Risk of Mitral Valve Prolapse in Taiwan Chinese

“…17) Identification of the locus for autosomal dominant myxomatous MVP to chromosome 16p11.2 -p12.1 was reported. 18) In addition, Xlinked inheritance has been reported in a special form of familial MVP, called myxomatous valvular dystrophy, which has been mapped to Xq28 in a large French pedigree. 19) Low blood pressure and autonomic dysfunction may be regarded as a phenotypic feature of MVP.…”

The mechanisms, diagnosis and management of mitral regurgitation in mitral valve prolapse and hypertrophic cardiomyopathy

“…19 Through chromosomal mapping, it has been shown that myxomatous MVP has a genetic heterogeneity which implies mutations located on chromosomes 16, 11 and 13. [20][21][22] Autosomal dominant and X-linked forms have also been cited. 19 Mutations of the fibrillin-1 (FBN1) gene which encodes the fibrillin-1 protein and mutations of the transforming growth factor β (TGF-β) receptor 2 gene are responsible for the occurrence of Marfan's syndrome, as well as MVP.…”

Promoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients

“…The exact cause of primary MVP is not completely understood but the contribution of genetic factors is evident. In some family studies, MVP has been linked to chromosomes 16p11.2-p12.1 [3], 11p15.4 [4] and 13q31.3-q32.1 [5]. Others have shown that polymorphisms in several genes are associated with an increased risk of MVP [6][7][8].…”