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. 2015 Dec 16;4(2):143-51.
doi: 10.1002/mgg3.187. eCollection 2016 Mar.

Next generation sequencing-based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Ozge Ceyhan-Birsoy  1 , Trevor J Pugh  2 , Mark J Bowser  3 , Elizabeth Hynes  3 , Ashley L Frisella  3 , Lisa M Mahanta  3 , Matt S Lebo  1 , Sami S Amr  1 , Birgit H Funke  4
Affiliations

Next generation sequencing-based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies

Ozge Ceyhan-Birsoy et al. Mol Genet Genomic Med. .

Abstract

Background: Diagnostic testing for genetic cardiomyopathies has undergone dramatic changes in the last decade with next generation sequencing (NGS) expanding the number of genes that can be interrogated simultaneously. Exon resolution copy number analysis is increasingly incorporated into routine diagnostic testing via cytogenomic arrays and more recently via NGS. While NGS is an attractive option for laboratories that have no access to array platforms, its higher false positive rate requires weighing the added cost incurred by orthogonal confirmation against the magnitude of the increase in diagnostic yield. Although copy number variants (CNVs) have been reported in various cardiomyopathy genes, their contribution has not been systematically studied.

Methods: We performed single exon resolution NGS-based deletion/duplication analysis for up to 46 cardiomyopathy genes in >1400 individuals with cardiomyopathies including HCM, DCM, ARVC, RCM, and LVNC.

Results and conclusion: Clinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders.

Keywords: Cardiomyopathies; DNA copy number variants; genetic heterogeneity; molecular diagnostics; next‐generation sequencing.

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