Mutation in mitral valve prolapse susceptible geneDCHS1causes familial mitral annular disjunction

Abstract

BackgroundMitral annular disjunction (MAD) is an under-recognised phenotype associated with severe ventricular arrhythmias. Limited knowledge has been gained on its molecular genesis.MethodsA total of 150 unrelated deceased Chinese were collected for whole-exome sequencing, with analysis focusing on a panel of 118 genes associated with ‘abnormal mitral valve morphology’. Cases were prespecified as ‘longitudinally extensive MAD (LE-MAD)’ or ‘longitudinally less-extensive MAD (LLE-MAD)’ according to the gross disjunctional length with a cut-off of 4.0 mm. The pedigree investigation was conducted on a case carrying an ultra-rare (minor allele frequency <0.1%) deleterious variant inDCHS1.ResultsSeventy-seven ultra-rare deleterious variants were finally identified. Exclusively, 12 ultra-rare deleterious variants distributed in nine genes occurred in LE-MAD, which wereANK1,COL3A1,DCHS1,FBN2,GNPTAB,LZTR1,PLD1,RYR1andVPS13B. Ultra-rare deleterious variants in those nine genes were predominantly distributed in LE-MAD compared with LLE-MAD (28% vs 5%, OR 7.30, 95% CI 2.33 to 23.38; p<0.001), and the only gene related to LE-MAD with borderline significance wasDCHS1. LE-MAD was consistently observed in a sizeable Chinese family, in which LE-MAD independently co-segregated with an ultra-rare deleterious variant inDCHS1, rs145429962.ConclusionThis study initially proposed that isolated LE-MAD might be a particular phenotype of MAD with a complex genetic predisposition. Deleterious variants inDCHS1might be associated with the morphogenesis of LE-MAD.