title: Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
abstract: The recent discovery of heterozygous human mutations that truncate full-length titin (TTN, an abundant structural, sensory, and signaling filament in muscle) as a common cause of end-stage dilated cardiomyopathy (DCM) promises new prospects for improving heart failure management. However, realization of this opportunity has been hindered by the burden of TTN-truncating variants (TTNtv) in the general population and uncertainty about their consequences in health or disease. To elucidate the effects of TTNtv, we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals across the spectrum of cardiac physiology and integrated these data with RNA and protein analyses of human heart tissues. We report diversity of TTN isoform expression in the heart, define the relative inclusion of TTN exons in different isoforms (using the TTN transcript annotations available at http://cardiodb.org/titin), and demonstrate that these data, coupled with the position of the TTNtv, provide a robust strategy to discriminate pathogenic from benign TTNtv. We show that TTNtv is the most common genetic cause of DCM in ambulant patients in the community, identify clinically important manifestations of TTNtv-positive DCM, and define the penetrance and outcomes of TTNtv in the general population. By integrating genetic, transcriptome, and protein analyses, we provide evidence for a length-dependent mechanism of disease. These data inform diagnostic criteria and management strategies for TTNtv-positive DCM patients and for TTNtv that are identified as incidental findings.
authors.affiliation: Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK. National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Angharad M
authors.initials: AM
authors.lastname: Roberts
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Ware
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Herman
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: John
authors.initials: J
authors.lastname: Baksi
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bick
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Buchan
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Roddy
authors.initials: R
authors.lastname: Walsh
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Shibu
authors.initials: S
authors.lastname: John
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Samuel
authors.initials: S
authors.lastname: Wilkinson
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mazzarotto
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Felkin
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Sungsam
authors.initials: S
authors.lastname: Gong
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Jacqueline A L
authors.initials: JA
authors.lastname: MacArthur
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Cunningham
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Flannick
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Altshuler
authors.affiliation: Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Macdonald
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.affiliation: Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Keogh
authors.affiliation: Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hayward
authors.affiliation: National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, UK.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Banner
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
authors.forename: Dudley J
authors.initials: DJ
authors.lastname: Pennell
authors.affiliation: Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
authors.forename: Declan P
authors.initials: DP
authors.lastname: O'Regan
authors.affiliation: National Heart Centre Singapore, Singapore 169609, Singapore.
authors.forename: Tan Ru
authors.initials: TR
authors.lastname: San
authors.affiliation: Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: de Marvao
authors.affiliation: Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
authors.forename: Timothy J W
authors.initials: TJ
authors.lastname: Dawes
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Ankur
authors.initials: A
authors.lastname: Gulati
authors.affiliation: National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Department of Medicine, University of Louisville and Jewish Hospital, Louisville, KY 40202, USA.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Birks
authors.affiliation: National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Radke
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany. German Centre for Cardiovascular Research, 13347 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA 01702, USA. Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Prasad
authors.affiliation: National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield National Health Service (NHS) Foundation Trust and Imperial College London, London SW3 6NP, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
authors.forename: Paul J R
authors.initials: PJ
authors.lastname: Barton
authors.affiliation: Cardiology Department, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
authors.affiliation: Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany. German Centre for Cardiovascular Research, 13347 Berlin, Germany. Charité-Universitätsmedizin, 10117 Berlin, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. stuart.cook@nhcs.com.sg cseidman@genetics.med.harvard.edu.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.affiliation: Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK. National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. National Heart Centre Singapore, Singapore 169609, Singapore. Duke-National University of Singapore, Singapore 169857, Singapore. stuart.cook@nhcs.com.sg cseidman@genetics.med.harvard.edu.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D064211:Connectin / Q000235:genetics* / Q000502:physiology; D005091:Exons; D014644:Genetic Variation; D064368:Healthy Volunteers; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000235:genetics / Q000628:therapy; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D064211:Connectin; D007136:Immunoglobulins; D020033:Protein Isoforms; C577285:TTN protein, human