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

Roberts, Angharad M and Ware, James S and Herman, Daniel S and Schafer, Sebastian and Baksi, John and Bick, Alexander G and Buchan, Rachel J and Walsh, Roddy and John, Shibu and Wilkinson, Samuel and Macdonald, Peter S and Keogh, Anne M and Hayward, Christopher S and Fatkin, Diane and Seidman, Jonathan G and Seidman, Christine E and Cook, Stuart A (2015) Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Science Translational Medicine, 7 (270). pp. 270ra6. ISSN 1946-6242 (PMC OA)

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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. (NHMRC grants)

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 25 Jan 2016 06:11
Last Modified: 09 May 2016 06:11
URI: http://eprints.victorchang.edu.au/id/eprint/228

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