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.
authors.affiliation: National Heart Centre Singapore, Singapore.|Duke-National University of Singapore, Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.affiliation: Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Antonio
authors.identifier: 0000-0001-9095-5887
authors.initials: A
authors.lastname: de Marvao
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Adami
authors.affiliation: Duke-National University of Singapore, Singapore.
authors.forename: Lorna R
authors.initials: LR
authors.lastname: Fiedler
authors.affiliation: National Heart Centre Singapore, Singapore.
authors.forename: Benjamin
authors.identifier: 0000-0001-8970-0932
authors.initials: B
authors.lastname: Ng
authors.affiliation: Duke-National University of Singapore, Singapore.
authors.forename: Ester
authors.initials: E
authors.lastname: Khin
authors.affiliation: Duke-National University of Singapore, Singapore.
authors.forename: Owen J L
authors.initials: OJ
authors.lastname: Rackham
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Heesch
authors.affiliation: National Heart Centre Singapore, Singapore.
authors.forename: Chee J
authors.initials: CJ
authors.lastname: Pua
authors.affiliation: Duke-National University of Singapore, Singapore.
authors.forename: Miao
authors.initials: M
authors.lastname: Kui
authors.affiliation: National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: Roddy
authors.initials: R
authors.lastname: Walsh
authors.affiliation: National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: Upasana
authors.initials: U
authors.lastname: Tayal
authors.affiliation: National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Prasad
authors.affiliation: Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Timothy J W
authors.initials: TJ
authors.lastname: Dawes
authors.affiliation: Duke-National University of Singapore, Singapore.
authors.forename: Nicole S J
authors.initials: NS
authors.lastname: Ko
authors.affiliation: National Heart Centre Singapore, Singapore.
authors.forename: David
authors.initials: D
authors.lastname: Sim
authors.affiliation: National Heart Centre Singapore, Singapore.
authors.forename: Laura L H
authors.initials: LL
authors.lastname: Chan
authors.affiliation: National Heart Centre Singapore, Singapore.|Duke-National University of Singapore, Singapore.
authors.forename: Calvin W L
authors.initials: CW
authors.lastname: Chin
authors.affiliation: National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzarotto
authors.affiliation: National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: Paul J
authors.identifier: 0000-0002-1165-7767
authors.initials: PJ
authors.lastname: Barton
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kreuchwig
authors.affiliation: Department of Surgery, National University of Singapore, Singapore.|Departments of Cardiology and Vascular Surgery, University Medical Center, Utrecht, the Netherlands.
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.affiliation: Department of Surgery, National University of Singapore, Singapore.
authors.forename: Teresa
authors.initials: T
authors.lastname: Totman
authors.affiliation: Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Biffi
authors.affiliation: National Heart Centre Singapore, Singapore.
authors.forename: Nicole
authors.initials: N
authors.lastname: Tee
authors.affiliation: Department of Computing, Imperial College London, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rueckert
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Schneider
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
authors.forename: Allison
authors.initials: A
authors.lastname: Faber
authors.affiliation: Institute of Gender in Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Goettingen, Germany.
authors.forename: Wolfgang A
authors.identifier: 0000-0003-0801-3773
authors.initials: WA
authors.lastname: Linke
authors.affiliation: Duke-National University of Singapore, Singapore.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Kovalik
authors.affiliation: Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: Declan
authors.identifier: 0000-0002-0691-0270
authors.initials: D
authors.lastname: O'Regan
authors.affiliation: Cardiovascular and Metabolic Disorders Program, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London, UK.|National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: James S
authors.identifier: 0000-0002-6110-5880
authors.initials: JS
authors.lastname: Ware
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.|Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: National Heart Centre Singapore, Singapore.|Duke-National University of Singapore, Singapore.|National Heart and Lung Institute and NIHR Royal Brompton Cardiovascular BRU, Imperial College London, London, UK.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D015331:Cohort Studies; D064211:Connectin / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006321:Heart / Q000502:physiology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051381:Rats
chemical_list: D064211:Connectin; C577285:TTN protein, human; C577295:Ttn protein, rat