Abstract
BackgroundA 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.Resultsp.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.ConclusionThis 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.
Highlights
Targeted sequencing of a locus linked to mitral valve prolapse (MVP) on chromosome 11p15.4 in four affected members of an extended family revealed protein-altering variants in the DCHS1 gene (Durst et al, 2015) (OMIM #603057)
The goal of this study is to investigate the presence of p.R2513H and p.R2330C in a series of unrelated French Canadian patients with MVP and to comprehensively screen the coding regions of DCHS1 to find other potentially deleterious variants
By sequencing exon 19 and part of exon 21 of DCHS1, we confirmed the absence of p.R2513H and p.R2330C in our population, but revealed two additional in silico-predicted deleterious variants: p.R2462Q and p.A2464P
Summary
Targeted sequencing of a locus linked to mitral valve prolapse (MVP) on chromosome 11p15.4 in four affected members of an extended family revealed protein-altering variants in the DCHS1 gene (Durst et al, 2015) (OMIM #603057). Dchs1-deficient mice (Dchs1+/À) exhibited mitral valve prolapse confirming that loss of function of this gene results in disease. A recent study identified DCHS1 as a causal gene for mitral valve prolapse. 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). 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
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