Research ArticleGenetic Medicine
Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease
- Angharad M. Roberts1,2,*,
- James S. Ware2,3,4,5,*,
- Daniel S. Herman4,5,6,*,
- Sebastian Schafer7,
- John Baksi2,
- Alexander G. Bick4,5,
- Rachel J. Buchan2,
- Roddy Walsh2,
- Shibu John2,
- Samuel Wilkinson2,
- Francesco Mazzarotto2,3,
- Leanne E. Felkin2,3,
- Sungsam Gong2,
- Jacqueline A. L. MacArthur8,
- Fiona Cunningham8,
- Jason Flannick5,9,
- Stacey B. Gabriel5,
- David M. Altshuler5,10,
- Peter S. Macdonald11,12,13,
- Matthias Heinig7,
- Anne M. Keogh11,12,13,
- Christopher S. Hayward11,12,13,
- Nicholas R. Banner3,14,
- Dudley J. Pennell2,3,
- Declan P. O’Regan1,
- Tan Ru San15,
- Antonio de Marvao1,
- Timothy J. W. Dawes1,
- Ankur Gulati2,
- Emma J. Birks3,16,
- Magdi H. Yacoub3,
- Michael Radke17,
- Michael Gotthardt17,18,
- James G. Wilson19,
- Christopher J. O’Donnell20,21,
- Sanjay K. Prasad2,
- Paul J. R. Barton2,3,
- Diane Fatkin11,12,13,
- Norbert Hubner7,18,22,
- Jonathan G. Seidman4,
- Christine E. Seidman4,5,23,24,†,‡ and
- Stuart A. Cook1,3,15,25,†,‡
- 1Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
- 2National 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.
- 3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
- 4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
- 5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
- 6Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
- 7Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
- 8European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
- 9Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
- 10Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
- 11Cardiology Department, St Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia.
- 12Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
- 13Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
- 14Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, UK.
- 15National Heart Centre Singapore, Singapore 169609, Singapore.
- 16Department of Medicine, University of Louisville and Jewish Hospital, Louisville, KY 40202, USA.
- 17Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
- 18German Centre for Cardiovascular Research, 13347 Berlin, Germany.
- 19Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
- 20National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA.
- 21Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
- 22Charité-Universitätsmedizin, 10117 Berlin, Germany.
- 23Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA.
- 24Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
- 25Duke–National University of Singapore, Singapore 169857, Singapore.
- ↵†Corresponding author. E-mail: stuart.cook{at}nhcs.com.sg (S.A.C.); cseidman{at}genetics.med.harvard.edu (C.E.S.)
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Science Translational Medicine 14 Jan 2015:
Vol. 7, Issue 270, pp. 270ra6
DOI: 10.1126/scitranslmed.3010134
Vol. 7, Issue 270, pp. 270ra6
DOI: 10.1126/scitranslmed.3010134
Angharad M. Roberts
1Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
2National 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.
James S. Ware
2National 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.
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Daniel S. Herman
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
6Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
Sebastian Schafer
7Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
John Baksi
2National 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.
Alexander G. Bick
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Rachel J. Buchan
2National 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.
Roddy Walsh
2National 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.
Shibu John
2National 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.
Samuel Wilkinson
2National 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.
Francesco Mazzarotto
2National 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.
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Leanne E. Felkin
2National 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.
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Sungsam Gong
2National 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.
Jacqueline A. L. MacArthur
8European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
Fiona Cunningham
8European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
Jason Flannick
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
9Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Stacey B. Gabriel
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
David M. Altshuler
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
10Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Peter S. Macdonald
11Cardiology Department, St Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia.
12Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
13Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Matthias Heinig
7Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
Anne M. Keogh
11Cardiology Department, St Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia.
12Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
13Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Christopher S. Hayward
11Cardiology Department, St Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia.
12Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
13Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Nicholas R. Banner
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
14Royal Brompton & Harefield NHS Foundation Trust, Harefield Hospital, Hill End Road, Harefield, Middlesex UB9 6JH, UK.
Dudley J. Pennell
2National 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.
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Declan P. O’Regan
1Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
Tan Ru San
15National Heart Centre Singapore, Singapore 169609, Singapore.
Antonio de Marvao
1Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
Timothy J. W. Dawes
1Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
Ankur Gulati
2National 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.
Emma J. Birks
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
16Department of Medicine, University of Louisville and Jewish Hospital, Louisville, KY 40202, USA.
Magdi H. Yacoub
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Michael Radke
17Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
Michael Gotthardt
17Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany.
18German Centre for Cardiovascular Research, 13347 Berlin, Germany.
James G. Wilson
19Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Christopher J. O’Donnell
20National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA.
21Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
Sanjay K. Prasad
2National 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.
Paul J. R. Barton
2National 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.
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
Diane Fatkin
11Cardiology Department, St Vincent’s Hospital, Darlinghurst, New South Wales 2010, Australia.
12Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
13Faculty of Medicine, University of New South Wales, Kensington, New South Wales 2052, Australia.
Norbert Hubner
7Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
18German Centre for Cardiovascular Research, 13347 Berlin, Germany.
22Charité-Universitätsmedizin, 10117 Berlin, Germany.
Jonathan G. Seidman
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Christine E. Seidman
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
5Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
23Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA.
24Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Stuart A. Cook
1Clinical Sciences Centre, Medical Research Council (MRC), Imperial College London, London W12 0NN, UK.
3National Heart & Lung Institute, Imperial College London, London SW3 6NP, UK.
15National Heart Centre Singapore, Singapore 169609, Singapore.
25Duke–National University of Singapore, Singapore 169857, Singapore.
