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

Ramchand, J, Wallis, M ORCID: 0000-0002-5441-1732, Macciocca, I, Lynch, E, Farouque, O, Martyn, M, Phelan, D, Chong, B, Lockwood, S, Weintraub, R, Thompson, Tina, Trainer, A, Zentner, D, Vohra, J, Chetrit, M, Hare, DL and James, P 2020 , 'Prospective evaluation of the utility of whole exome sequencing in dilated cardiomyopathy' , American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease, vol. 9, no. 2 , pp. 1-11 , doi:

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Background: Dilated cardiomyopathy may be heritable but shows extensive genetic heterogeneity. The utility of whole exomesequencing as a first-line genetic test for patients with dilated cardiomyopathy in a contemporary “real-world” setting has not beenspecifically established. Using whole exome sequencing with rigorous, evidence-based variant interpretation, we aimed to identifythe 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 dilatedcardiomyopathy. Variants were prioritized for curation in up to 247 genes and classified using American College of Medical Geneticsand Genomics–based criteria. Ten (12%) had a pathogenic or likely pathogenic variant. Eight (10%) participants had truncating TTNvariants classified as variants of uncertain significance. Five (6%) participants had variants of unknown significance according tostrict American College of Medical Genetics and Genomics criteria but classified as either pathogenic or likely pathogenic by otherclinical laboratories. Pathogenic or likely pathogenic variants were found in 8 genes (all within tier 1 genes), 2 (20%) of which are notincluded in a standard commercially available dilated cardiomyopathy panel. Using our bioinformatics pipeline, there was an averageof 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 stringentclassification using American College of Medical Genetics and Genomics criteria, the rate of detection of pathogenic variants islower than previous reports. Efforts to improve adherence to these guidelines will be important to prevent erroneousmisclassification of nonpathogenic variants in dilated cardiomyopathy genetic testing and inappropriate cascade screening.

Item Type: Article
Authors/Creators: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, Tina and Trainer, A and Zentner, D and Vohra, J and Chetrit, M and Hare, DL and James, P
Keywords: cardiomyopathy, whole exome sequencing, clinical exome, next generation sequencing
Journal or Publication Title: American Heart Association. Journal. Cardiovascular and Cerebrovascular Disease
Publisher: Wiley-Blackwell Publishing, Inc.
ISSN: 2047-9980
DOI / ID Number:
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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.

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