Abstract

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in 1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.

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Acknowledgements

We thank all the patients and healthy volunteers for taking part in this research and our team of research nurses across the hospital sites. We also thank M. von Frieling-Salewsky for technical support. The research was supported by the MRC Clinical Sciences Centre, UK, to J.S.W., S.A.C., A.d.M. and D.P.O'R., the NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton, the Harefield NHS Foundation Trust and Imperial College London to J.S.W. and S.A.C., the NIHR Imperial Biomedical Research Centre, British Heart Foundation, UK (SP/10/10/28431, PG/12/27/29489) to S.A.C., D.P.O'R. and C.B., the Wellcome Trust, UK (107469/Z/15/Z to J.S.W., 087183/Z/08/Z, 092854/Z/10/Z and WT095908), a Wellcome Trust Fellowship (100211/Z/12/Z and P43579_WMET to T.J.W.D.), Fondation Leducq to J.S.W., the Tanoto Foundation to S.A.C., CORDA, the National Institutes of Health (NHLBI 2R01HL080494 to J.G.S. and C.E.S.), the National Medical Research Council (NMRC) Singapore (CIRG13nov024 and STaR13nov002 to D.P.V.d.K.), the SingHealth Duke–NUS Institute of Precision Medicine, the Rosetrees Trust, the Health Innovation Challenge Fund (HICF-R6-373 to J.S.W.) funding from the Wellcome Trust and the Department of Health, UK, the Howard Hughes Medical Institute, the European Union EURATRANS award (HEALTH-F4-2010-241504 to N.H.), the Helmholtz Alliance ICEMED to N.H., European Union FP7 (CardioNeT-ITN-289600 to F.M.), Deutsche Forschungsgemeinschaft (SFB1002, TPA08 to W.A.L., Forschergruppe 1054 HU 1522/1-1 to N.H. and TP1 to V.R.-Z.), and an EMBO Long-Term Fellowship (ALTF 186-2015 to S.v.H.) and Marie Curie Actions (LTFCOFUND2013, GA-2013-609409 to S.v.H.). This publication includes independent research commissioned by the Health Innovation Challenge Fund (HICF), a parallel funding partnership between the UK Department of Health and the Wellcome Trust. The views expressed in this work are those of the authors and not necessarily those of the UK Department of Health or the Wellcome Trust.

Author information

Author notes

    • Sebastian Schafer
    •  & Antonio de Marvao

    These authors contributed equally to this work.

    • James S Ware
    • , Norbert Hubner
    •  & Stuart A Cook

    These authors jointly supervised this work.

Affiliations

  1. National Heart Centre Singapore, Singapore.

    • Sebastian Schafer
    • , Benjamin Ng
    • , Chee J Pua
    • , David Sim
    • , Laura L H Chan
    • , Calvin W L Chin
    • , Nicole Tee
    •  & Stuart A Cook
  2. Duke–National University of Singapore, Singapore.

    • Sebastian Schafer
    • , Lorna R Fiedler
    • , Ester Khin
    • , Owen J L Rackham
    • , Miao Kui
    • , Nicole S J Ko
    • , Calvin W L Chin
    • , Jean-Paul Kovalik
    •  & Stuart A Cook
  3. Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.

    • Antonio de Marvao
    • , Timothy J W Dawes
    • , Carlo Biffi
    • , Declan O'Regan
    •  & James S Ware
  4. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

    • Eleonora Adami
    • , Sebastiaan van Heesch
    • , Franziska Kreuchwig
    • , Valentin Schneider
    • , Allison Faber
    •  & Norbert Hubner
  5. National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.

    • Roddy Walsh
    • , Upasana Tayal
    • , Sanjay K Prasad
    • , Francesco Mazzarotto
    • , Paul J Barton
    • , James S Ware
    •  & Stuart A Cook
  6. Department of Surgery, National University of Singapore, Singapore.

    • Dominique P V de Kleijn
    •  & Teresa Totman
  7. Departments of Cardiology and Vascular Surgery, University Medical Center, Utrecht, the Netherlands.

    • Dominique P V de Kleijn
  8. Department of Computing, Imperial College London, London, UK.

    • Daniel Rueckert
  9. Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Vera Regitz-Zagrosek
  10. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.

    • Vera Regitz-Zagrosek
    •  & Norbert Hubner
  11. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Jonathan G Seidman
    •  & Christine E Seidman
  12. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Christine E Seidman
  13. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Christine E Seidman
  14. Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.

    • Wolfgang A Linke
  15. DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Goettingen, Germany.

    • Wolfgang A Linke
  16. Charité Universitätsmedizin, Berlin, Germany.

    • Norbert Hubner

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Contributions

S.A.C. conceived, managed and arranged funding for the project. A.d.M., E.A., L.R.F., B.N., E.K., S.v.H., C.J.P., U.T., S.K.P., T.J.W.D., N.S.J.K., D.S., L.L.H.C., C.W.L.C., P.J.B., D.P.V.d.K., T.T., C.B., N.T., V.R.-Z., J.G.S., C.E.S. and W.A.L. performed experiments and contributed clinical data. S.S., A.d.M., O.J.L.R., M.K., R.W., F.M., F.K., D.R., V.S., A.F., J.-P.K., D.P.O'R., J.S.W., N.H. and S.A.C. performed data analysis and interpretation. S.S., B.N. and S.A.C. prepared the manuscript with input from co-authors.

Competing interests

S.A.C. consults for Illumina.

Corresponding author

Correspondence to Stuart A Cook.

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  1. 1.

    3D cardiac imaging shows the effect of TTNtv on human left ventricular geometry.

    Mass univariate regression models show the relationship between TTNtv genotype (cardiac exons with PSI > 15%) and increasing endocardial volume (positive coefficients) in end systole (left) and end diastole (right). Standardized β coefficients are plotted on the endocardial surface with outlines of left (red) and right (blue) ventricles. The area enclosed by the yellow contour has a corrected P <0.05 (multiple linear regression).

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https://doi.org/10.1038/ng.3719

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