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

Sebastian Schafer; Antonio De Marvao; Eleonora Adami; Lorna R. Fiedler; Benjamin Ng; Ester Khin; Owen J.L. Rackham; Sebastiaan Van Heesch; Chee J. Pua; Miao Kui; Roddy Walsh; Upasana Tayal; Sanjay K. Prasad; Timothy J.W. Dawes; Nicole S.J. Ko; David Sim; Laura L.H. Chan; Calvin W.L. Chin; Francesco Mazzarotto; Paul J. Barton; Franziska Kreuchwig; Dominique P.V. De Kleijn; Teresa Totman; Carlo Biffi; Nicole Tee; Daniel Rueckert; Valentin Schneider; Allison Faber; Vera Regitz-Zagrosek; Jonathan G. Seidman; Christine E. Seidman; Wolfgang A. Linke; Jean Paul Kovalik; Declan O'Regan; James S. Ware; Norbert Hubner; Stuart A. Cook

doi:10.1038/ng.3719

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

Sebastian Schafer, Antonio De Marvao, Eleonora Adami, Lorna R. Fiedler, Benjamin Ng, Ester Khin, Owen J.L. Rackham, Sebastiaan Van Heesch, Chee J. Pua, Miao Kui, Roddy Walsh, Upasana Tayal, Sanjay K. Prasad, Timothy J.W. Dawes, Nicole S.J. Ko, David Sim, Laura L.H. Chan, Calvin W.L. Chin, Francesco Mazzarotto, Paul J. BartonFranziska Kreuchwig, Dominique P.V. De Kleijn, Teresa Totman, Carlo Biffi, Nicole Tee, Daniel Rueckert, Valentin Schneider, Allison Faber, Vera Regitz-Zagrosek, Jonathan G. Seidman, Christine E. Seidman, Wolfgang A. Linke, Jean Paul Kovalik, Declan O'Regan, James S. Ware, Norbert Hubner, Stuart A. Cook

Research output: Contribution to journal › Article › peer-review

243 Scopus citations

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.

Original language	English
Pages (from-to)	46-53
Number of pages	8
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3719
State	Published - 1 Jan 2017
Externally published	Yes

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Schafer, S., De Marvao, A., Adami, E., Fiedler, L. R., Ng, B., Khin, E., Rackham, O. J. L., Van Heesch, S., Pua, C. J., Kui, M., Walsh, R., Tayal, U., Prasad, S. K., Dawes, T. J. W., Ko, N. S. J., Sim, D., Chan, L. L. H., Chin, C. W. L., Mazzarotto, F., ... 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

@article{847c2f46d17b41b79cfcf5bdb30f8c14,

title = "Titin-truncating variants affect heart function in disease cohorts and the general population",

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.",

author = "Sebastian Schafer and {De Marvao}, Antonio and Eleonora Adami and Fiedler, {Lorna R.} and Benjamin Ng and Ester Khin and Rackham, {Owen J.L.} and {Van Heesch}, Sebastiaan and Pua, {Chee J.} and Miao Kui and Roddy Walsh and Upasana Tayal and Prasad, {Sanjay K.} and Dawes, {Timothy J.W.} and Ko, {Nicole S.J.} and David Sim and Chan, {Laura L.H.} and Chin, {Calvin W.L.} and Francesco Mazzarotto and Barton, {Paul J.} and Franziska Kreuchwig and {De Kleijn}, {Dominique P.V.} and Teresa Totman and Carlo Biffi and Nicole Tee and Daniel Rueckert and Valentin Schneider and Allison Faber and Vera Regitz-Zagrosek and Seidman, {Jonathan G.} and Seidman, {Christine E.} and Linke, {Wolfgang A.} and Kovalik, {Jean Paul} and Declan O'Regan and Ware, {James S.} and Norbert Hubner and Cook, {Stuart A.}",

year = "2017",

month = jan,

day = "1",

doi = "10.1038/ng.3719",

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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, 'Titin-truncating variants affect heart function in disease cohorts and the general population', Nature Genetics, vol. 49, no. 1, pp. 46-53. https://doi.org/10.1038/ng.3719

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T1 - Titin-truncating variants affect heart function in disease cohorts and the general population

AU - Schafer, Sebastian

AU - De Marvao, Antonio

AU - Adami, Eleonora

AU - Fiedler, Lorna R.

AU - Ng, Benjamin

AU - Khin, Ester

AU - Rackham, Owen J.L.

AU - Van Heesch, Sebastiaan

AU - Pua, Chee J.

AU - Kui, Miao

AU - Walsh, Roddy

AU - Tayal, Upasana

AU - Prasad, Sanjay K.

AU - Dawes, Timothy J.W.

AU - Ko, Nicole S.J.

AU - Sim, David

AU - Chan, Laura L.H.

AU - Chin, Calvin W.L.

AU - Mazzarotto, Francesco

AU - Barton, Paul J.

AU - Kreuchwig, Franziska

AU - De Kleijn, Dominique P.V.

AU - Totman, Teresa

AU - Biffi, Carlo

AU - Tee, Nicole

AU - Rueckert, Daniel

AU - Schneider, Valentin

AU - Faber, Allison

AU - Regitz-Zagrosek, Vera

AU - Seidman, Jonathan G.

AU - Seidman, Christine E.

AU - Linke, Wolfgang A.

AU - Kovalik, Jean Paul

AU - O'Regan, Declan

AU - Ware, James S.

AU - Hubner, Norbert

AU - Cook, Stuart A.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

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DO - 10.1038/ng.3719

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JO - Nature Genetics

JF - Nature Genetics

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ER -

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

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