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Modern genomic techniques in the identification of genetic causes of cardiomyopathy
  1. Timothy F Spracklen1,2,
  2. Bernard Keavney3,
  3. Nakita Laing4,
  4. Ntobeko Ntusi1,5,
  5. Gasnat Shaboodien1
  1. 1 Cape Heart Institute, University of Cape Town Department of Medicine, Cape Town, South Africa
  2. 2 Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa
  3. 3 Division of Cardiovascular Sciences, The University of Manchester, Manchester, UK
  4. 4 Division of Human Genetics, University of Cape Town, Cape Town, South Africa
  5. 5 Department of Medicine, University of Cape Town, Cape Universities Body Imaging Centre, Cape Town, South Africa
  1. Correspondence to Professor Gasnat Shaboodien, Cape Heart Institute, University of Cape Town Department of Medicine, Cape Town, Western Cape, South Africa; gasnat.shaboodien{at}


Over the past three decades numerous disease-causing genes have been linked to the pathogenesis of heritable cardiomyopathies, but many causal genes are yet to be identified. Next-generation sequencing (NGS) platforms have revolutionised clinical testing capacity in familial cardiomyopathy. In this review, we summarise how NGS technologies have advanced our understanding of genetic non-syndromic cardiomyopathy over the last decade. First, 26 putative new disease-causing genes have been identified to date, mostly from whole-exome sequencing, and some of which (FLNC, MTO1, HCN4) have had a considerable clinical impact and are now included in routine diagnostic gene panels. Second, we consider challenges in variant interpretation and the importance of large-scale NGS population control cohorts for this purpose. Third, an emerging role of common variation in some forms of genetic cardiomyopathy is being elucidated through recent studies which have illustrated an additive effect of numerous polymorphic loci on cardiac parameters; this may explain phenotypic variability and low rates of genetic diagnosis from sequencing studies. Finally, we discuss the clinical utility of genetic testing in cardiomyopathy in Western settings, where NGS panel testing of core disease genes is currently recommended with possible implications for patient management. Given the findings of recent studies, whole-exome or whole-genome sequencing should be considered in patients of non-European ancestry with clearly familial disease, or severe paediatric disease, when no result is obtained on panel sequencing. The clinical utility of polygenic risk assessment needs to be investigated further in patients with unexplained dilated cardiomyopathy and hypertrophic cardiomyopathy in whom a pathogenic variant is not identified.

  • genetics
  • cardiomyopathies
  • genetic diseases
  • inborn

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  • Contributors All authors approved the submission of this manuscript to Heart.

  • Funding GS and NN gratefully acknowledge support from the National Research Foundation (grant numbers 95627 and 105923) and the Medical Research Council of South Africa (grant number 416006 and 416071). In addition, NN also acknowledges support from the Harry Crossley Foundation and Lily and Ernst Hausmann Trust. BK is supported by a British Heart Foundation personal chair and would also like to acknowledge UKRI Global Challenges Research Fund Grant (reference number ES/N01393X/1).

  • 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.