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.
- Cardiovascular Abnormalities
Data availability statement
Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable.
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NZ and QZ contributed equally.
Deceased Prof. Cheng died on Dec. 15, 2022
Correction notice This article has been corrected since it was published online first. The funding statement has been added.
Contributors This project was designed and guided by JC and YC, who were the guarantors responsible for the overall content. NZ and RL conducted the pedigree investigation, while RC and QW were responsible for DNA extraction and sequencing. NZ and QZ collated necropsy records and interpreted sequencing data. NZ wrote this manuscript, which QZ, JC and YC revised.
Funding This work was supported by the National Natural Science Foundation of China [81920108021, 81970200, 82271609, 81901919] and the Guangzhou Municipal Science and Technology Project (2023B01J1011).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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