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

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Item Type:	Article
Title:	Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease
Creators Name:	Roberts, A.M., Ware, J.S., Herman, D.S., Schafer, S., Baksi, J., Bick, A.G., Buchan, R.J., Walsh, R., John, S., Wilkinson, S., Mazzarotto, F., Felkin, L.E., Gong, S., MacArthur, J.A.L., Cunningham, F., Flannick, J., Gabriel, S.B., Altshuler, D.M., Macdonald, P.S., Heinig, M., Keogh, A.M., Hayward, C.S., Banner, N.R., Pennell, D.J., O'Regan, D.P., San, T.R., de Marvao, A., Dawes, T.J.W., Gulati, A., Birks, E.J., Yacoub, M.H., Radke, M., Gotthardt, M., Wilson, J.G., O'Donnell, C.J., Prasad, S.K., Barton, P.J.R., Fatkin, D., Hubner, N., Seidman, J.G., Seidman, C.E. and Cook, S.A.
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.
Keywords:	Alleles, Cohort Studies, Connectin, Dilated Cardiomyopathy, Exons, Genetic Transcription, Genetic Variation, Healthy Volunteers, Heart, Heart Failure, Immunoglobulins, Mutation, Protein Isoforms
Source:	Science Translational Medicine
ISSN:	1946-6234
Publisher:	American Association for the Advancement of Science
Volume:	7
Number:	270
Page Range:	270ra6
Date:	14 January 2015
Additional Information:	Copyright © 2015, American Association for the Advancement of Science.
Official Publication:	https://doi.org/10.1126/scitranslmed.3010134
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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