Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 270, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3010134
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Categories
Funding
- NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust
- 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 Trus
- European Community's Seventh Framework Programme (FP7 [GEN2PHEN project]) [CardioNeT-ITN-289600, 200754]
- National Human Genome Research Institute [U54 HG003067]
- NIH [HL080494, 5-T32-GM007748-33]
- Howard Hughes Medical Institute
- Australian National Health and Medical Research Council
- NHLBI [N01-HC-25195, 6R01-NS 17950, N01-HC-95170, N01-HC-95171, N01-HC-95172, HL-102924]
- National Institute for Minority Health and Health Disparities
- National Institute of Biomedical Imaging and Bioengineering
- U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]
- MRC [MC_U120085815] Funding Source: UKRI
- Wellcome Trust [092854/Z/10/Z, 087183/Z/08/Z] Funding Source: Wellcome Trust
- Academy of Medical Sciences (AMS) [AMS-SGCL9-Ware] Funding Source: researchfish
- British Heart Foundation [SP/10/10/28431, PG/12/27/29489, FS/13/13/29819] Funding Source: researchfish
- Heart Research UK [RG2596] Funding Source: researchfish
- Medical Research Council [MC_U120085815] Funding Source: researchfish
- National Institute for Health Research [ACF-2010-18-002, NF-SI-0508-10081] Funding Source: researchfish
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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.
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