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Genotype-phenotype correlations
Original research
Mutation in mitral valve prolapse susceptible gene DCHS1 causes familial mitral annular disjunction
  1. Nan Zhou1,2,3,4,5,
  2. Qianhao Zhao1,2,
  3. Rui Li1,2,
  4. Ruofei Cheng1,2,
  5. Qiuping Wu6,
  6. Jianding Cheng1,2,
  7. Yangxin Chen3,4,5
  1. 1Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
  2. 2Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Sun Yat-Sen University, Guangzhou, Guangdong, China
  3. 3Department of Cardiology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China
  4. 4Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China
  5. 5Guangzhou Key Laboratory of Molecular Mechanisms and Translation in Major Cardiovascular Disease, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
  6. 6Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong, China
  1. Correspondence to Professor Yangxin Chen, Department of Cardiology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong 510120, China; chenyx39{at}mail.sysu.edu.cn; Professor Jianding Cheng, Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; chengjd{at}mail.sysu.edu.cn

Abstract

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.

  • Cardiology
  • Cardiovascular Abnormalities

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable.

https://doi.org/10.1136/jmg-2023-109278

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    Data availability statement

    Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable.

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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.