Please use this identifier to cite or link to this item: https://doi.org/10.1126/scitranslmed.3010134
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dc.titleIntegrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease
dc.contributor.authorRoberts A.M.
dc.contributor.authorWare J.S.
dc.contributor.authorHerman D.S.
dc.contributor.authorSchafer S.
dc.contributor.authorBaksi J.
dc.contributor.authorBick A.G.
dc.contributor.authorBuchan R.J.
dc.contributor.authorWalsh R.
dc.contributor.authorJohn S.
dc.contributor.authorWilkinson S.
dc.contributor.authorMazzarotto F.
dc.contributor.authorFelkin L.E.
dc.contributor.authorGong S.
dc.contributor.authorMacarthur J.A.L.
dc.contributor.authorCunningham F.
dc.contributor.authorFlannick J.
dc.contributor.authorGabriel S.B.
dc.contributor.authorAltshuler D.M.
dc.contributor.authorMacDonald P.S.
dc.contributor.authorHeinig M.
dc.contributor.authorKeogh A.M.
dc.contributor.authorHayward C.S.
dc.contributor.authorBanner N.R.
dc.contributor.authorPennell D.J.
dc.contributor.authorO'Regan D.P.
dc.contributor.authorSan T.R.
dc.contributor.authorDe Marvao A.
dc.contributor.authorDawes T.J.W.
dc.contributor.authorGulati A.
dc.contributor.authorBirks E.J.
dc.contributor.authorYacoub M.H.
dc.contributor.authorRadke M.
dc.contributor.authorGotthardt M.
dc.contributor.authorWilson J.G.
dc.contributor.authorO'Donnell C.J.
dc.contributor.authorPrasad S.K.
dc.contributor.authorBarton P.J.R.
dc.contributor.authorFatkin D.
dc.contributor.authorHubner N.
dc.contributor.authorSeidman J.G.
dc.contributor.authorSeidman C.E.
dc.contributor.authorCook S.A.
dc.date.accessioned2019-01-15T09:17:56Z
dc.date.available2019-01-15T09:17:56Z
dc.date.issued2015
dc.identifier.citationRoberts 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., Cook S.A. (2015). Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Science Translational Medicine 7 (270) : 270ra6. ScholarBank@NUS Repository. https://doi.org/10.1126/scitranslmed.3010134
dc.identifier.issn19466234
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/150864
dc.description.abstractThe 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 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.
dc.publisherAmerican Association for the Advancement of Science
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1126/scitranslmed.3010134
dc.description.sourcetitleScience Translational Medicine
dc.description.volume7
dc.description.issue270
dc.description.page270ra6
dc.published.statePublished
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