RT Journal Article SR Electronic T1 Mutation in mitral valve prolapse susceptible gene DCHS1 causes familial mitral annular disjunction JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmg-2023-109278 DO 10.1136/jmg-2023-109278 A1 Zhou, Nan A1 Zhao, Qianhao A1 Li, Rui A1 Cheng, Ruofei A1 Wu, Qiuping A1 Cheng, Jianding A1 Chen, Yangxin YR 2023 UL http://jmg.bmj.com/content/early/2023/07/05/jmg-2023-109278.abstract AB Background Mitral annular disjunction (MAD) is an under-recognised phenotype associated with severe ventricular arrhythmias. Limited knowledge has been gained on its molecular genesis.Methods A 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 in DCHS1.Results Seventy-seven ultra-rare deleterious variants were finally identified. Exclusively, 12 ultra-rare deleterious variants distributed in nine genes occurred in LE-MAD, which were ANK1, COL3A1, DCHS1, FBN2, GNPTAB, LZTR1, PLD1, RYR1 and VPS13B. 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 was DCHS1. LE-MAD was consistently observed in a sizeable Chinese family, in which LE-MAD independently co-segregated with an ultra-rare deleterious variant in DCHS1, rs145429962.Conclusion This study initially proposed that isolated LE-MAD might be a particular phenotype of MAD with a complex genetic predisposition. Deleterious variants in DCHS1 might be associated with the morphogenesis of LE-MAD.Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable.