Advertisement

Genetic arrhythmias complicating patients with dilated cardiomyopathy

  • Zongzhe Li
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
  • Peng Chen
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
  • Chenze Li
    Affiliations
    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
  • Lun Tan
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Jinchao Xu
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
  • Hong Wang
    Affiliations
    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
  • Yang Sun
    Affiliations
    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
  • Yan Wang
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Chunxia Zhao
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Search for articles by this author
  • Mark S. Link
    Affiliations
    Division of Cardiology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
    Search for articles by this author
  • Arthur A.M. Wilde
    Affiliations
    Amsterdam UMC, University of Amsterdam, Heart Center Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
    Search for articles by this author
  • Dao Wu Wang
    Correspondence
    Dr. Dao Wu Wang, State Key Laboratory of Reproductive Medicine, The Center for Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China.
    Affiliations
    The Center for Clinical Reproductive Medicine and Department of Cardiology, State Key Laboratory of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
    Search for articles by this author
  • Dao Wen Wang
    Correspondence
    Address reprint requests and correspondence: Dr. Dao Wen Wang, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China.
    Affiliations
    Division of Cardiology, Departments of Internal Medicine and Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China
    Search for articles by this author
Published:September 12, 2019DOI:https://doi.org/10.1016/j.hrthm.2019.09.012

      Background

      Sudden cardiac death due to malignant arrhythmias is a common cause of death in dilated cardiomyopathy (DCM). Whether genetic variants increase the risk of arrhythmias in DCM is unknown.

      Objective

      The purpose of this study was to investigate the genetic causes of arrhythmias in DCM patients.

      Methods

      Whole-exome sequencing and high-depth targeted next-generation sequencing (142-gene panel) were used. Eight specific DCM pedigrees with arrhythmias and 2 separate cohorts of 1232 consecutive unrelated sporadic DCM patients from 3 medical centers (550 in the discovery cohort, 682 in the replication cohort) were analyzed; 470 (250 in the discovery cohort, 220 in the replication cohort) suffered from arrhythmias (DCM-A group) and 762 (300 in the discovery cohort, 462 in the replication cohort) did not (DCM-NA group). All identified causative variants were Sanger sequenced to eliminate false-positive results and then screened in 700 unrelated matched arrhythmia- and DCM-free healthy controls.

      Results

      We identified long QT syndrome (LQTS)-causative variants that independently cosegregated in 2 unrelated DCM-LQTS pedigrees. Pathogenic variants in arrhythmia-related genes (ion channelopathies) were identified in 4.9% (23/470) of sporadic DCM-A patients (4.0% in the discovery cohort, 5.9% in the replication cohort) but only 0.1% (1/762) of sporadic DCM-NA patients (P = 2.16 × 10–9). These arrhythmia-related pathogenic variants included long QT syndrome, atrial fibrillation, sick sinus syndrome, cardiac conduction disease, and Brugada syndrome.

      Conclusion

      Some arrhythmias in DCM patients are caused by arrhythmia-related pathogenic variants. For DCM patients with explicit arrhythmias, arrhythmia-causative genetic screening may help to explain the etiology and decision-making.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Heart Rhythm
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hershberger R.E.
        • Hedges D.J.
        • Morales A.
        Dilated cardiomyopathy: the complexity of a diverse genetic architecture.
        Nat Rev Cardiol. 2013; 10: 531-547
        • Elliott P.
        • Andersson B.
        • Arbustini E.
        • et al.
        Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
        Eur Heart J. 2008; 29: 270-276
        • Towbin J.A.
        • Bowles N.E.
        The failing heart.
        Nature. 2002; 415: 227-233
        • John R.
        • Rajasinghe H.A.
        • Chen J.M.
        • et al.
        Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy.
        Ann Thorac Surg. 2001; 72: 440-449
        • Fatkin D.
        Guidelines for the diagnosis and management of familial dilated cardiomyopathy.
        Heart Lung Circ. 2011; 20: 691-693
        • Akinrinade O.
        • Ollila L.
        • Vattulainen S.
        • et al.
        Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy.
        Eur Heart J. 2015; 36: 2327-2337
        • Hershberger R.E.
        • Lindenfeld J.
        • Mestroni L.
        • Seidman C.E.
        • Taylor M.R.
        • Towbin J.A.
        Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline.
        J Card Fail. 2009; 15: 83-97
        • Disertori M.
        • Quintarelli S.
        • Mazzola S.
        • Favalli V.
        • Narula N.
        • Arbustini E.
        The need to modify patient selection to improve the benefits of implantable cardioverter-defibrillator for primary prevention of sudden death in non-ischaemic dilated cardiomyopathy.
        Europace. 2013; 15: 1693-1701
        • Czosek R.J.
        • Jefferies J.L.
        • Khoury P.R.
        • et al.
        Arrhythmic burden and ambulatory monitoring of pediatric patients with cardiomyopathy.
        Pacing Clin Electrophysiol. 2016; 39: 443-451
        • Moss A.J.
        • Zareba W.
        • Hall W.J.
        • et al.
        Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction.
        N Engl J Med. 2002; 346: 877-883
        • Bardy G.H.
        • Lee K.L.
        • Mark D.B.
        • et al.
        Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
        N Engl J Med. 2005; 352: 225-237
        • Epstein A.E.
        • DiMarco J.P.
        • Ellenbogen K.A.
        • et al.
        2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities.
        Circulation. 2013; 127: e283-e352
        • Epstein A.E.
        • Dimarco J.P.
        • Ellenbogen K.A.
        • et al.
        ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities.
        Heart Rhythm. 2008; 5: e1-e62
        • Russo A.M.
        • Stainback R.F.
        • Bailey S.R.
        • et al.
        ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy.
        J Am Coll Cardiol. 2013; 61: 1318-1368
        • van Rijsingen I.A.
        • Arbustini E.
        • Elliott P.M.
        • et al.
        Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study.
        J Am Coll Cardiol. 2012; 59: 493-500
        • Diegoli M.
        • Grasso M.
        • Favalli V.
        • et al.
        Diagnostic work-up and risk stratification in X-linked dilated cardiomyopathies caused by dystrophin defects.
        J Am Coll Cardiol. 2011; 58: 925-934
        • Kumar S.
        • Baldinger S.H.
        • Gandjbakhch E.
        • et al.
        Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers.
        J Am Coll Cardiol. 2016; 68: 2299-2307
        • van Spaendonck-Zwarts K.Y.
        • van Rijsingen I.A.
        • van den Berg M.P.
        • et al.
        Genetic analysis in 418 index patients with idiopathic dilated cardiomyopathy: overview of 10 years' experience.
        Eur J Heart Fail. 2013; 15: 628-636
        • Sale H.
        • Wang J.
        • O'Hara T.J.
        • et al.
        Physiological properties of hERG 1a/1b heteromeric currents and a hERG 1b-specific mutation associated with long-QT syndrome.
        Circ Res. 2008; 103: e81-e95
        • Kapplinger J.D.
        • Tester D.J.
        • Salisbury B.A.
        • et al.
        Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.
        Heart Rhythm. 2009; 6: 1297-1303
        • Ohno S.
        • Zankov D.P.
        • Yoshida H.
        • et al.
        N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome.
        Heart Rhythm. 2007; 4: 332-340
        • Du C.
        • El Harchi A.
        • Zhang H.
        • Hancox J.C.
        Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition.
        Physiol Rep. 2013; 1: e00175
        • Kokunai Y.
        • Nakata T.
        • Furuta M.
        • et al.
        A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.
        Neurology. 2014; 82: 1058-1064
        • Yang Y.
        • Yang Y.
        • Liang B.
        • et al.
        Identification of a Kir3.4 mutation in congenital long QT syndrome.
        Am J Hum Genet. 2010; 86: 872-880
        • Haas J.
        • Frese K.S.
        • Peil B.
        • et al.
        Atlas of the clinical genetics of human dilated cardiomyopathy.
        Eur Heart J. 2015; 36: 1123-1135a
        • Yang Y.
        • Li J.
        • Lin X.
        • et al.
        Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation.
        J Hum Genet. 2009; 54: 277-283
        • Hayashi K.
        • Konno T.
        • Tada H.
        • et al.
        Functional characterization of rare variants implicated in susceptibility to lone atrial fibrillation.
        Circ Arrhythm Electrophysiol. 2015; 8: 1095-1104
        • Yang Y.Q.
        • Lin X.P.
        • Li J.
        • Chen Y.H.
        Identification and functional analysis of a KCNA5 mutation responsible for idiopathic atrial fibrillation.
        Zhonghua Yi Xue Za Zhi. 2010; 90: 1100-1104
        • Yang Y.
        • Xia M.
        • Jin Q.
        • et al.
        Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation.
        Am J Hum Genet. 2004; 75: 899-905
        • Koo S.H.
        • Ho W.F.
        • Lee E.J.
        Genetic polymorphisms in KCNQ1, HERG, KCNE1 and KCNE2 genes in the Chinese, Malay and Indian populations of Singapore.
        Br J Clin Pharmacol. 2006; 61: 301-308
        • Liu W.
        • Deng J.
        • Wang G.
        • et al.
        KCNE2 modulates cardiac L-type Ca(2+) channel.
        J Mol Cell Cardiol. 2014; 72: 208-218
        • Wang F.
        • Liu J.
        • Hong L.
        • et al.
        The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R).
        Heart Rhythm. 2013; 10: 1500-1506
        • Chen Y.H.
        • Xu S.J.
        • Bendahhou S.
        • et al.
        KCNQ1 gain-of-function mutation in familial atrial fibrillation.
        Science. 2003; 299: 251-254
        • Xia M.
        • Jin Q.
        • Bendahhou S.
        • et al.
        A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.
        Biochem Biophys Res Commun. 2005; 332: 1012-1019
        • Lieve K.V.
        • Williams L.
        • Daly A.
        • et al.
        Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.
        Genet Test Mol Biomarkers. 2013; 17: 553-561