Review Article | Published:

Role of titin in cardiomyopathy: from DNA variants to patient stratification

Nature Reviews Cardiology volume 15, pages 241252 (2018) | Download Citation


Dilated cardiomyopathy (DCM) affects approximately 1 in 250 individuals and is the leading indication for heart transplantation. DCM is often familial, and the most common genetic predisposition is a truncating variation in the giant sarcomeric protein, titin, which occurs in up to 15% of ambulant patients with DCM and 25% of end-stage or familial cases. In this article, we review the evidence for the role of titin truncation in the pathogenesis of DCM and our understanding of the molecular mechanisms and pathophysiological consequences of variation in the gene encoding titin (TTN). Such variation is common in the general population (up to 1% of individuals), and we consider key features that discriminate variants with disease-causing potential from those that are benign. We summarize strategies for clinical interpretation of genetic variants for use in the diagnosis of patients and the evaluation of their relatives. Finally, we consider the contemporary and potential future role for genetic stratification in cardiomyopathy and in the general population, evaluating titin variation as a predictor of outcome and treatment response for precision medicine.

Key points

  • Titin-truncating variants (TTNtv) are strongly associated with dilated cardiomyopathy (DCM), but are also prevalent in the general population

  • TTNtv identified through genetic testing of patients with confirmed DCM might be clinically actionable and informative for the management of probands and their families

  • The relevance of TTNtv identified through sequencing for other indications is not well defined; such variants can be associated with increased risk of DCM, but in aggregate are not highly penetrant

  • Haploinsufficiency caused by TTNtv does not clearly explain all the associated molecular and physiological consequences, suggesting that other mechanisms also contribute to disease pathogenesis

  • Important genetic and environmental determinants of TTNtv penetrance and expressivity remain to be identified

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The authors thank Zofia T. Bilinska (Cardinal Stefan Wyszynski Institute of Cardiology, Warsaw, Poland) for providing access to the data for Figure 4, and acknowledge support from the British Heart Foundation; Fondation Leducq; Medical Research Council, UK; National Medical Research Council Singapore; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; NIHR Royal Brompton Biomedical Research Unit; SingHealth Duke–National University Singapore (Duke–NUS) Institute of Precision Medicine; and Wellcome Trust (107469/Z/15/Z).

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  1. National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.

    • James S. Ware
    •  & Stuart A. Cook
  2. Medical Research College (MRC) London Institute of Medical Sciences, Du Cane Road, London W12 0NN, UK.

    • James S. Ware
    •  & Stuart A. Cook
  3. Duke–National University of Singapore (Duke–NUS) Medical School and National Heart Centre Singapore, 8 College Road, 169857, Singapore.

    • Stuart A. Cook


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J.S.W. and S.A.C. researched data for the article, discussed the content, wrote the manuscript, and reviewed and/or edited the article before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to James S. Ware or Stuart A. Cook.

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    Assigning risk and causality to genetic variants.

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