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

Title: Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease.
Authors: Roberts, AM
Ware, JS
Herman, DS
Schafer, S
Baksi, J
Bick, AG
Buchan, RJ
Walsh, R
John, S
Wilkinson, S
Mazzarotto, F
Felkin, LE
Gong, S
L MacArthur, JA
Cunningham, F
Flannick, J
Gabriel, SB
Altshuler, DM
Macdonald, PS
Heinig, M
Keogh, AM
Hayward, CS
Banner, NR
Pennell, DJ
O'Regan, DP
San, TR
De Marvao, A
W Dawes, TJ
Gulati, A
Birks, EJ
Yacoub, MH
Radke, M
Gotthardt, M
Wilson, JG
O'Donnell, CJ
Prasad, SK
Barton, PJ
Fatkin, D
Hubner, N
Seidman, JG
Seidman, CE
Cook, SA
Item Type: Journal Article
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.
Issue Date: 14-Jan-2015
Date of Acceptance: 25-Nov-2014
URI: http://hdl.handle.net/10044/1/85882
DOI: 10.1126/scitranslmed.3010134
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science
Start Page: 270ra6
End Page: 270ra6
Journal / Book Title: Science Translational Medicine
Volume: 7
Issue: 270
Copyright Statement: © 2015, American Association for the Advancement of Science.
Sponsor/Funder: British Heart Foundation
British Heart Foundation
Heart Research UK
Commission of the European Communities
British Heart Foundation
British Heart Foundation
Funder's Grant Number: PG/09/074/27961
PG/12/27/29489
RG2596/11/13
289600
SP/10/10/28431
FS/13/13/29819
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
CARDIOVASCULAR MAGNETIC-RESONANCE
FAMILIAL DILATED CARDIOMYOPATHY
HEART-FAILURE
PROGNOSTIC VALUE
RISK-FACTORS
POPULATION
VARIANTS
MUTATIONS
SEQUENCE
GENES
Adolescent
Adult
Aged
Alleles
Cardiomyopathy, Dilated
Cohort Studies
Connectin
Exons
Genetic Variation
Healthy Volunteers
Heart
Heart Failure
Humans
Immunoglobulins
Middle Aged
Mutation
Protein Isoforms
Transcription, Genetic
Young Adult
Heart
Humans
Cardiomyopathy, Dilated
Immunoglobulins
Protein Isoforms
Cohort Studies
Transcription, Genetic
Mutation
Alleles
Exons
Adolescent
Adult
Aged
Middle Aged
Heart Failure
Genetic Variation
Young Adult
Healthy Volunteers
Connectin
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Conference Place: United States
Open Access location: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560092/
Appears in Collections:Imaging Sciences
Department of Medicine (up to 2019)