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Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse.

ABSTRACT: BACKGROUND:A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. METHODS:DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico. RESULTS:p.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases. CONCLUSION:This study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk.

SUBMITTER: Clemenceau A

PROVIDER: S-EPMC5823682 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse.

Clemenceau Alisson A Bérubé Jean-Christophe JC Bélanger Paméla P Gaudreault Nathalie N Lamontagne Maxime M Toubal Oumhani O Clavel Marie-Annick MA Capoulade Romain R Mathieu Patrick P Pibarot Philippe P Bosse Yohan Y

Molecular genetics & genomic medicine 20171210 1

<h4>Background</h4>A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation.<h4>Methods</h4>DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in s ...[more]

PMID: 29224215

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Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

Dataset Information

Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse.

Publications

Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse.

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