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Sci Transl Med. 2015 Jan 14;7(270):270ra6. doi: 10.1126/scitranslmed.3010134.

Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.

Author information

1
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.
2
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.
3
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.
4
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
5
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.
6
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
7
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.
8
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
9
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
10
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
11
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.
12
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.
13
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.
14
Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
15
National Heart Centre Singapore, Singapore 169609, Singapore.
16
National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK. Department of Medicine, University of Louisville and Jewish Hospital, Louisville, KY 40202, USA.
17
National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
18
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
19
Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany. German Centre for Cardiovascular Research, 13347 Berlin, Germany.
20
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
21
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.
22
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.
23
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
24
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.
25
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.

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.

Comment in

PMID:
25589632
PMCID:
PMC4560092
DOI:
10.1126/scitranslmed.3010134
[Indexed for MEDLINE]
Free PMC Article

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