Mutations in DCHS1 cause mitral valve prolapse.

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

A locus for autosomal dominant mitral valve prolapse on chromosome 11p15.4.

Mitral valve prolapse (MVP) is a common cardiovascular abnormality in the United States, occurring in approximately 2.4% of the general population. Clinically, patients with MVP exhibit fibromyxomatous changes in one or both of the mitral leaflets that result in superior displacement of the leaflets into the left atrium. Although often clinically benign, MVP can be associated with important accompanying sequelae, including mitral regurgitation, bacterial endocarditis, congestive heart failure, atrial fibrillation, and even sudden death. MVP is genetically heterogeneous and is inherited as an autosomal dominant trait that exhibits both sex- and age-dependent penetrance. In this report, we describe the results of a genome scan and show that a locus for MVP maps to chromosome 11p15.4. Multipoint parametric analysis performed by use of GENEHUNTER gave a maximum LOD score of 3.12 for the chromosomal region immediately surrounding the four-marker haplotype D11S4124-D11S2349-D11S1338-D11S1323, and multipoint nonparametric analysis (NPL) confirms this finding (NPL=38.59; P=.000397). Haplotype analysis across this region defines a 4.3-cM region between the markers D11S1923 and D11S1331 as the location of a new MVP locus, MMVP2, and confirms the genetic heterogeneity of this disorder. The discovery of genes involved in the pathogenesis of this common disease is crucial to understanding the marked variability in disease expression and mortality seen in MVP.

Mitral valve prolapse in the general population: the benign nature of echocardiographic features in the Framingham Heart Study.

OBJECTIVE: The aim of this study was to examine the echocardiographic features and associations of mitral valve prolapse (MVP) diagnosed by current two-dimensional echocardiographic criteria in an unselected outpatient sample. BACKGROUND: Previous studies of patients with MVP have emphasized the frequent occurrence of echocardiographic abnormalities such as significant mitral regurgitation (MR) and left atrial (LA) enlargement that are associated with clinical complications. These studies, however, have been limited by the use of hospital-based or referral series. METHODS: We quantitatively studied all 150 subjects with possible MVP by echocardiography and 150 age- and gender-matched subjects without MVP from the 3,491 subjects in the Framingham Heart Study. Based on leaflet morphology, subjects were classified as having classic (n = 46), nonclassic (n = 37), or no MVP. RESULTS: Leaflet length, MR degree, and LA and left ventricular size were significantly but mildly increased in MVP (p < 0.0001 to 0.004), with mean values typically within normal range. Average MR jet area was 15.1 +/- 1.4% (mild) in classic MVP and 8.9 +/- 1.5% (trace) in nonclassic MVP; MR was severe in only 3 of 46 (6.5%) subjects with classic MVP, and LA volume was increased in only 8.7% of those with classic MVP and 2.7% of those with nonclassic MVP. CONCLUSIONS: Although the echocardiographic characteristics of subjects with MVP in the Framingham Heart Study differ from those without MVP, they display a far more benign profile of associated valvular, atrial, and ventricular abnormalities than previously reported in hospital- or referral-based series. Therefore, these findings may influence the perception of and approach to the outpatient with MVP.