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Prospective evaluation of the utility of whole exome sequencing in dilated cardiomyopathy


Ramchand, J and Wallis, M and Macciocca, I and Lynch, E and Farouque, O and Martyn, M and Phelan, D and Chong, B and Lockwood, S and Weintraub, R and Thompson, T and Trainer, A and Zentner, D and Vohra, J and Chetrit, M and Hare, DL and James, P, Prospective evaluation of the utility of whole exome sequencing in dilated cardiomyopathy, American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, 9, (2) pp. 1-11. ISSN 2047-9980 (2020) [Refereed Article]

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Copyright Statement

Copyright 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License, ( which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

DOI: doi:10.1161/JAHA.119.013346


Background: Dilated cardiomyopathy may be heritable but shows extensive genetic heterogeneity. The utility of whole exome sequencing as a first-line genetic test for patients with dilated cardiomyopathy in a contemporary "real-world" setting has not been specifically established. Using whole exome sequencing with rigorous, evidence-based variant interpretation, we aimed to identify the prevalence of a molecular diagnosis in patients with dilated cardiomyopathy in a clinical setting.

Methods and Results: Whole exome sequencing was performed in eligible patients (n=83) with idiopathic or familial dilated cardiomyopathy. Variants were prioritized for curation in up to 247 genes and classified using American College of Medical Genetics and Genomics-based criteria. Ten (12%) had a pathogenic or likely pathogenic variant. Eight (10%) participants had truncating TTN variants classified as variants of uncertain significance. Five (6%) participants had variants of unknown significance according to strict American College of Medical Genetics and Genomics criteria but classified as either pathogenic or likely pathogenic by other clinical laboratories. Pathogenic or likely pathogenic variants were found in 8 genes (all within tier 1 genes), 2 (20%) of which are not included in a standard commercially available dilated cardiomyopathy panel. Using our bioinformatics pipeline, there was an average of 0.74 variants of uncertain significance per case with ~0.75 person-hours needed to interpret each of these variants.

Conclusions: Whole exome sequencing is an effective diagnostic tool for patients with dilated cardiomyopathy. With stringent classification using American College of Medical Genetics and Genomics criteria, the rate of detection of pathogenic variants is lower than previous reports. Efforts to improve adherence to these guidelines will be important to prevent erroneous misclassification of nonpathogenic variants in dilated cardiomyopathy genetic testing and inappropriate cascade screening.

Item Details

Item Type:Refereed Article
Keywords:cardiomyopathy, whole exome sequencing, clinical exome, next generation sequencing
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Genomics
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Wallis, M (Dr Mathew Wallis)
ID Code:145729
Year Published:2020
Web of Science® Times Cited:15
Deposited By:UTAS Centre for Rural Health
Deposited On:2021-08-04
Last Modified:2022-09-05
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