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

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

254 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	46-53
Aantal pagina's	8
Tijdschrift	Nature Genetics
Volume	49
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/ng.3719
Status	Gepubliceerd - jan. 2017
Extern gepubliceerd	Ja

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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{7a9448d42eaf4ae29055e68b06d69839,

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% 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.",

keywords = "Animals, Cardiomyopathy, Dilated/genetics, Case-Control Studies, Cohort Studies, Connectin/genetics, Genetic Variation/genetics, Heart/physiology, High-Throughput Nucleotide Sequencing, Humans, Male, Rats",

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 Jean-Paul Kovalik and Declan O'Regan and Ware, {James S} and Norbert Hubner and Cook, {Stuart A}",

year = "2017",

month = jan,

doi = "10.1038/ng.3719",

language = "English",

volume = "49",

pages = "46--53",

journal = "Nature Genetics",

issn = "1061-4036",

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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, J-P, 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, nr. 1, blz. 46-53. https://doi.org/10.1038/ng.3719

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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

Y1 - 2017/1

N2 - 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.

AB - 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.

KW - Animals

KW - Cardiomyopathy, Dilated/genetics

KW - Case-Control Studies

KW - Cohort Studies

KW - Connectin/genetics

KW - Genetic Variation/genetics

KW - Heart/physiology

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Male

KW - Rats

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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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