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.

Keywords: DCHS1; deleterious variants; genetics; mitral valve prolapse; sequencing.

Figure 1

Identification and characterization of genetic variants in the DCHS1 gene in patients affected by mitral valve prolapse. (a) Sequence chromatograms of the novel (p.A2464P) and rare (p.R2462Q and p.R2770Q) missense in silico‐predicted deleterious variants identified in this study with two‐dimensional echocardiographic long‐axis view of a representative heterozygote patient for each variant. The blue line denotes the mitral annulus. (b) The exon–intron structure of the DCHS1 gene and the localization of the identified genetic variants. The coding exons are shown in black (or red) and the untranslated regions in gray. The regions of the gene sequenced among the 100 patients are in red. Genetic variants are illustrated with their rs numbers if available with genotyping counts in parentheses for 12 or 100 patients. Red dots illustrate the six in silico‐predicted deleterious variants. The two functional variants identified by Durst et al. (2015) on exons 19 and 21 are illustrated on top in black with an asterisk. Missense and synonymous variants identified in this study are indicated in red and black, respectively. Newly and rare identified variants with no rs number are illustrated in green and named based on standard gene mutation nomenclature (den Dunnen et al., 2016). (c) Summary of patients carrying at least one of six variants identified and considered deleterious in this study. Heterozygote carriers are identified by a yellow box