Mitral Valve Prolapse 2

A number sign (#) is used with this entry because of evidence that mitral valve prolapse-2 (MVP2) can be caused by heterozygous mutation in the DCHS1 gene (603057.0004).

Description

Patients with MVP2 have nonsyndromic MVP of variable severity inherited as an autosomal dominant trait.

For a general phenotypic description and discussion of genetic heterogeneity of mitral valve prolapse, see MVP1 (157700).

Clinical Features

Freed et al. (2003) examined a large 5-generation family in which at least 12 members had mitral valve prolapse with no extracardiac manifestations of connective tissue abnormalities or Marfan syndrome (154700).

Durst et al. (2015) studied 2 unrelated families with MVP due to mutation in the DCHS1 gene (see MOLECULAR GENETICS). In the first family, a brother and sister exhibited classic MVP. The brother underwent mitral valve repair for severe regurgitation at age 21 years, with resected valve tissue showing myxomatous degeneration. The proband's 27-year-old sister had thickened leaflets and moderate regurgitation. Their mother and maternal grandfather both had mild MVP. In the second family, the female proband had moderate to severe heart failure due to severe mitral regurgitation with posterior leaflet prolapse which was surgically repaired at age 72 years. She had 1 son and 1 daughter who were also diagnosed with MVP, whereas another son had indeterminate MVP status, due to tethering of his leaflets down into the left ventricular cavity by mild left inferior wall hypokinesis, which masks leaflet prolapse motion towards the left atrium.

Mapping

In a large 5-generation family segregating mitral valve prolapse, Freed et al. (2003) found linkage of the disorder to a locus (MVP2) on 11p15.4. Multipoint parametric analysis gave a maximum lod score of 3.12 for the chromosomal region immediately surrounding a 4-marker haplotype; multipoint nonparametric analysis confirmed this finding (NPL = 38.59; p = 0.000397). Haplotype analysis defined a 4.3-cM region between the markers D11S1923 and D11S1331.

Molecular Genetics

Using DNA from 4 affected individuals from the 5-generation family with MVP mapping to chromosome 11p15, previously studied by Freed et al. (2003), Durst et al. (2015) performed capture sequencing of the linked interval and identified a missense mutation in the DCHS1 gene (R2513H; 603057.0004) that segregated with disease in the family and was not found in the NHLBI Exome Sequencing Project database. Screening of a cohort of MVP patients revealed 2 additional families in which a different DCHS1 missense mutation (R2330C; 603057.0005) segregated with disease.

Animal Model

Durst et al. (2015) performed morpholino knockdown of the zebrafish homolog dachsous1b and observed development of a cardiac atrioventricular canal defect that could be rescued by wildtype but not mutant DCHS1. Homozygous knockout of Dchs1 in mice resulted in neonatal lethality and multiorgan impairment, but Dchs1 +/- mice showed mitral valve prolapse with pronounced involvement of the posterior leaflet, which was elongated and shifted the leaflet coaptation anteriorly. Histologic analysis confirmed leaflet thickening and showed myxomatous degeneration with increased proteoglycan accumulation in both mitral leaflets.