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.

Figure 1

Echocardiogram of one subject (individual IV.1, kindred 1) with MMVP. a, Two-dimensional echocardiogram in the parasternal long-axis view. The arrow indicates the displacement of the mitral leaflets above the line connecting the midportions of the annular hinge points (shown as a dashed line). RV=right ventricle; LV=left ventricle; Ao=aorta; LA=left atrium; and PML=posterior mitral leaflet. b, M-mode recording in the parasternal long-axis view. The arrow indicates the increased thickness of the AML. Its measurement is performed in the midportion of the leaflet and is shown as a dashed line.

Figure 2

Pedigrees of four families with MMVP. Females are designated by circles and males are designated by squares. Affected subjects are shown as blackened symbols; individuals whose phenotype was uncertain are shown as gray symbols; unaffected individuals are shown as unblackened symbols; unphenotyped obligate carriers are indicated by a dot within the symbol; and deceased individuals are indicated by a diagonal line across the symbol. Paternal and maternal haplotypes are indicated on the right and left sides, respectively. a, Haplotypes of kindred 1 formed with 10 markers between D16S3103 and D16S3093. b, Haplotypes of kindred 2 formed with 10 markers between D16S423 and D16S3093. c, Genetic status of individuals from kindreds 3 and 4.

Figure 3

Refined location of the MMVP-1 locus. A multipoint linkage analysis comparing the segregation of MMVP and 20 marker loci was performed with the assumption of two modes of inheritance. Only families that showed linkage to D16S3068 (kindreds 1 and 2) were included in this analysis. The map of marker loci used and the distances in centimorgans are indicated below the plots of multipoint LOD score; the full curve indicates LOD score calculated with the conservative model and the dotted line indicates LOD score calculated with the stringent model; a bar represents the 1-LOD-unit support interval for the location of MMVP-1.