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Nat Genet. 2017 Jan;49(1):46-53. doi: 10.1038/ng.3719. Epub 2016 Nov 21.

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

Author information

1
National Heart Centre Singapore, Singapore.
2
Duke-National University of Singapore, Singapore.
3
Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
4
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
5
National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
6
Department of Surgery, National University of Singapore, Singapore.
7
Departments of Cardiology and Vascular Surgery, University Medical Center, Utrecht, the Netherlands.
8
Department of Computing, Imperial College London, London, UK.
9
Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
10
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
11
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
12
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
13
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
14
Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.
15
DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Goettingen, Germany.
16
Charité Universitätsmedizin, Berlin, Germany.

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.

PMID:
27869827
PMCID:
PMC5201198
DOI:
10.1038/ng.3719
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

S.A.C. consults for Illumina.

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