Titin-truncating variants affect heart function in disease cohorts and the general population

Schafer S, De Marvao A, Adami E, Fiedler LR, Ng B, Khin E, Rackham OJL, Van Heesch S, Pua CJ, Kui M, Walsh R, Tayal U, Prasad SK, Dawes TJW, Ko NSJ, Sim D, Chan LLH, Chin CWL, Mazzarotto F, Barton PJ, Kreuchwig F, De Kleijn DPV, Totman T, Biffi C, Tee N, Rueckert D, Schneider V, Faber A, Regitz-Zagrosek V, Seidman JG, Seidman CE, Linke WA, Kovalik JP, O'Regan D, Ware JS, Hubner N, Cook SA (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Nature Genetics Nature Publishing Group

Book Volume: 49

Pages Range: 46-53

Journal Issue: 1

DOI: 10.1038/ng.3719

Abstract

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in 1/41% 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.

Involved external institutions

National Heart Research Institute Singapore (NHRIS) SG Singapore (SG) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) National University of Singapore (NUS) SG Singapore (SG) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE) Harvard University US United States (USA) (US) Ruhr-Universität Bochum (RUB) DE Germany (DE)

How to cite

APA:

Schafer, S., De Marvao, A., Adami, E., Fiedler, L.R., Ng, B., Khin, E.,... Cook, S.A. (2017). Titin-truncating variants affect heart function in disease cohorts and the general population. Nature Genetics, 49(1), 46-53. https://doi.org/10.1038/ng.3719

MLA:

Schafer, Sebastian, et al. "Titin-truncating variants affect heart function in disease cohorts and the general population." Nature Genetics 49.1 (2017): 46-53.

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