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Original research article
Heritability in genetic heart disease: the role of genetic background
  1. Joeri A Jansweijer1,
  2. Karin Y van Spaendonck-Zwarts2,
  3. Michael W T Tanck3,
  4. J Peter van Tintelen2,4,
  5. Imke Christiaans2,
  6. Jasper van der Smagt5,
  7. Alexa Vermeer2,
  8. J Martijn Bos6,
  9. Arthur J Moss7,
  10. Heikki Swan8,
  11. Sylvia Priori9,
  12. Annika Rydberg10,
  13. Jacob Tfelt-Hansen11,
  14. Michael Ackerman6,
  15. Iacopo Olivotto12,
  16. Philippe Charron13,
  17. Juan R Gimeno14,
  18. Maarten van den Berg15,
  19. Arthur Wilde1,16 and
  20. Yigal M Pinto1
  1. 1Heart Center, Clinical and Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
  2. 2Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
  3. 3Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
  4. 4Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
  5. 5Department of Medical Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands
  6. 6Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
  7. 7Department of Cardiovascular Medicine, Mayo Clinic, Rochester, New York, USA
  8. 8Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland
  9. 9Department of Molecular Medicine, University of Pavia, Pavia, Italy
  10. 10Department of Clinical Sciences, Umeå University, Umeå, Sweden
  11. 11Department of Cardiology, Copenhagen University Hospital, Copenhagen, Denmark
  12. 12Department of Cardiology, Careggi University Hospital, Florence, Italy
  13. 13Department of Clinical Genetics, Hopital Ambroise-Pare, Boulogne-Billancourt, France
  14. 14Department of Cardiology, Universitary Hospital Virgen Arrixaca, El Palmar, Murcia, Spain
  15. 15Department of Cardiology, University Medical Center Groningen, Groningen, Netherlands
  16. 16Centre of Excellence in Research of Hereditary Disorders, Princess Al-Jawhara Al-Brahim, Jeddah, Saudi Arabia
  1. Correspondence to Dr Joeri A Jansweijer; j.a.jansweijer{at}


Background Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or ‘modifier genes’. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins.

Methods We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy.

Results Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy.

Conclusions Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.

  • Genetics
  • Twin Study
  • Cardiomyopathy
  • Channelopathy

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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  • Correction notice This article has been corrected since it first published online. The open access licence type has been amended.

  • Contributors Planning: JJ, KYvS-Z, AW, YMP. Conduct: JJ, KYvS-Z, MWTT, JPvT, IC, JvdS, AV, JMB, AJM, HS, SP, BT, PR, AR, UBD, JT-H, MA, IO, PC, JRG, EJWR, MvdB, AW, YMP. Reporting: JJ, KYvS-Z, MWTT, JPvT, MA, AW, YMP. Overall: JJ, KYvS-Z, YMP.

  • Funding This work was supported by the Netherlands CardioVascular Research Initiative (Project PREDICT and ARENA): the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, the Royal Netherlands Academy of Sciences, the Windland Smith Rice Comprehensive Sudden Cardiac Death Program, the Finnish Foundation for Cardiovascular Research and the Novo Nordic Foundation.

  • Competing interests MA is a consultant for Boston Scientific, Gilead Sciences, Medtronic and St. Jude Medical. MA and Mayo Clinic received sales-based royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests. However, these entities had no involvement with this study. The remaining authors have nothing to disclose.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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