Reassessment of genes associated with dilated and hypertrophic cardiomyopathy in a Chinese Han population

Abstract

Introduction: More than 100 genes are reportedly associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). However, the situation that many genes lack of reassessment in a large population hinders the interpretations of these genes in genetic diagnostic testing. Moreover, limited genetic data for cardiomyopathy in Chinese patients was reported.

Aim: Therefore, here we reassessed an estimated 500 putative genes in the Chinese Han population by whole exome sequencing (WES) to describe the landscape of variants in these genes and to confirm their genetic contribution to DCM and HCM.

Methods and Results: WES was performed in 1059 DCM patients, 1175 HCM patients and 514 controls. Approximately 500 candidate genes were selected for evaluation. Truncating variants of TTN and MYBPC3 were the most burdensome for both groups. Gene-based association tests identified 35 and 35 genes associated with DCM and HCM, respectively. Except for the known genes of cardiomyopathy, the top three genes associated with DCM were MUC16, KMT2C, and FBN1, while the top three genes associated with HCM were KMT2C, RYR2, and SCN5A. After filtering for pathogenicity, FBN1 is still significantly associated with DCM and SCN5A and RYR2 remains significantly enriched in HCM patients. However, after adjustment, only TTN with DCM and MYBPC3 and MYH7 with HCM remains significant.

Conclusion: We described the genetic landscape of Chinese patients with DCM and HCM and developed a website (www.cardioexome.cn) to enable open access to this information. Furthermore, the gene-based association test confirmed the contribution of TTN to DCM and MYBPC3 and MYH7 to HCM in Chinese Han. In addition, the website, www.cardioexome.cn, was developed to store these sequencing results.

Keywords

Dilated Cardiomyopathy / hypertrophic cardiomyopathy / whole exome sequencing / gene-based association / case-control study

References

[1] McNally EM.Dilated cardiomyopathy: genetic determinants and mechanisms.Circ Res2017;121:731-48 PMCID:PMC5626020

[2] Marian AJ.Hypertrophic cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy.Circ Res2017;121:749-70 PMCID:PMC5654557

[3] Mazzarotto F,Buchan RJ.Reevaluating the genetic contribution of monogenic dilated cardiomyopathy.Circulation2020;141:387-98 PMCID:PMC7004454

[4] Walsh R,Wilk A.Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes.Eur Heart J2017;38:3461-8 PMCID:PMC5837460

[5] Pinto YM,Arbustini E.Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases.Eur Heart J2016;37:1850-8

[6] Ommen SR,Burke MA.2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the american college of cardiology/American heart association joint committee on clinical practice guidelines.J Am Coll Cardiol2020;76:e159-240

[7] Dai J,Huang W.RBM20 is a candidate gene for hypertrophic cardiomyopathy.Can J Cardiol2021;37:1751-9

[8] McKenna A,Banks E.The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res2010;20:1297-303 PMCID:PMC2928508

[9] Bolger AM,Usadel B.Trimmomatic: a flexible trimmer for illumina sequence data.Bioinformatics2014;30:2114-20 PMCID:PMC4103590

[10] Wang K,Hakonarson H.ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res2010;38:e164 PMCID:PMC2938201

[11] Jagadeesh KA,Berger MJ.M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity.Nat Genet2016;48:1581-6

[12] Ioannidis NM,Pejaver V.REVEL: an ensemble method for predicting the pathogenicity of rare missense variants.Am J Hum Genet2016;99:877-85 PMCID:PMC5065685

[13] Rehm HL,Brooks LD.ClinGen-the clinical genome resource.N Engl J Med2015;372:2235-42 PMCID:PMC4474187

[14] Xiao L,Sun Y.Clinical significance of variants in the TTN gene in a large cohort of patients with sporadic dilated cardiomyopathy.Front Cardiovasc Med2021;8:657689 PMCID:PMC8120103

[15] Jiang DS,Li R.The histone methyltransferase mixed lineage leukemia (MLL)3 may play a potential role on clinical dilated cardiomyopathy.Mol Med2017;23:196-203 PMCID:PMC5630473

[16] Ansari KI.Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing.FEBS J2010;277:1790-804

[17] Amorim S,Moura B.The role of biomarkers in dilated cardiomyopathy: assessment of clinical severity and reverse remodeling.Rev Port Cardiol2017;36:709-16

[18] Karaca O,Guler E.Serum carbohydrate antigen 125 levels in nonischemic dilated cardiomyopathy: a useful biomarker for prognosis and functional mitral regurgitation.Congest Heart Fail2012;18:144-50

[19] Tan L,Zhou C.FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection.Hum Mol Genet2017;26:4814-22

[20] Wang JJ,Sun Y,Wang DW.FBN1 Splice-altering mutations in marfan syndrome: a case report and literature review.Genes2022;13:1842 PMCID:PMC9602130

[21] Landstrom AP,Wehrens XHT.Calcium signaling and cardiac arrhythmias.Circ Res2017;120:1969-93 PMCID:PMC5607780

[22] Alvarado FJ,Yuchi Z.Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2.JCI Insight2019;5:126544 PMCID:PMC6483635