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

Angharad M. Roberts, James S. Ware, Daniel S. Herman, Sebastian Schafer, John Baksi, Alexander G. Bick, Rachel J. Buchan, Roddy Walsh, Shibu John, Samuel Wilkinson, Francesco Mazzarotto, Leanne E. Felkin, Sungsam Gong, Jacqueline A.L. Macarthur, Fiona Cunningham, Jason Flannick, Stacey B. Gabriel, David M. Altshuler, Peter S. MacDonald, Matthias HeinigAnne M. Keogh, Christopher S. Hayward, Nicholas R. Banner, Dudley J. Pennell, Declan P. O'Regan, Tan Ru San, Antonio De Marvao, Timothy J.W. Dawes, Ankur Gulati, Emma J. Birks, Magdi H. Yacoub, Michael Radke, Michael Gotthardt, James G. Wilson, Christopher J. O'Donnell, Sanjay K. Prasad, Paul J.R. Barton, Diane Fatkin, Norbert Hubner, Jonathan G. Seidman, Christine E. Seidman, Stuart A. Cook

Research output: Contribution to journalArticlepeer-review

343 Scopus citations


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 (T TNtv) 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, 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.

Original languageEnglish
Article number270ra6
JournalScience Translational Medicine
Issue number270
StatePublished - Jan 14 2015

Bibliographical note

Funding Information:
We thank all the patients, healthy volunteers, and participants in the FHS, JHS, and WHI for taking part in this research, and our team of research nurses across the hospital sites. Funding: The research was supported by the NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust and Imperial College London, NIHR Imperial Biomedical Research Centre, British Heart Foundation UK (SP/10/10/28431, PG/12/27/29489), European Molecular Biology Laboratory, MRC UK, Wellcome Trust UK (087183/Z/08/Z, 092854/Z/10/Z, WT095908), Fondation Leducq, Tanoto Foundation, Goh Foundation, Academy of Medical Sciences, Arthritis Research UK, Heart Research UK, CORDA, National Medical Research Council (NMRC) Singapore, Rosetrees Trust, European Community's Seventh Framework Programme (FP7) [CardioNeT-ITN-289600; 200754 - the GEN2PHEN project], National Human Genome Research Institute (U54 HG003067), NIH (HL080494, 5-T32-GM007748-33), Howard Hughes Medical Institute, and the Australian National Health and Medical Research Council. The FHS was supported by the NHLBI (N01-HC-25195, 6R01-NS 17950), and genotyping services from Affymetrix Inc. (N02-HL-6-4278). The JHS is supported by NHLBI (N01-HC-95170, N01-HC-95171, N01-HC-95172), the National Institute for Minority Health and Health Disparities, and the National Institute of Biomedical Imaging and Bioengineering. The WHI Sequencing Project is supported by NHLBI (HL-102924), NIH, and U.S. Department of Health and Human Services through contracts N01WH22110

ASJC Scopus subject areas

  • General Medicine


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