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

Abstract

BackgroundDiagnostic 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.MethodsWe 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 ConclusionClinically 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.

Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice

“…Regarding cardiomyopathies, we detected a frequency of CNVs in our series of: 1.2% for HCM, 4.4% for DCM, 5.1% for AC, and 3.4% for LVNC. Recently, Ceyhan-Birsoy et al published a study of similar characteristics and reported the following frequencies: 0.56% for HCM, 0.6% for DCM, 1% for AC, and 1.9% for LVNC [17]. Lopes et al also published in 2015 a comprehensive screening for CNVs in HCM patients, and reported a frequency of 0.8% [13].…”

“…Several studies have identified CNVs as causative of cardiac diseases associated with SCD [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. However, exhaustive analysis of multiple genes in large cohorts of patients has never been performed for most SCD-related diseases.…”

“…In the last years, several authors consider a CNV any imbalance larger than 50 base pairs [3] (bp) (this latter criterion is the one followed in the present work). Evidence supporting a role of CNVs in SCD-related pathologies has been reported, but robust studies with large cohorts of patients and multiple genes being screened have only been performed for specific SCD-related diseases [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults

“…In addition, our analysis at the time did not include CNV. The applicability of CNV analysis in clinical cardiovascular genetics, however, remains undetermined 38 . Despite all our efforts, there are always potentials for false positive results.…”

Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1

“…Copy number variants (CNVs) were identified via an NGS‐based detection tool (VisCap) (Pugh et al, ), but were only available for 23 patients in the derivation cohort and 281 patients in the validation cohort due to NGS data quality. Confirmation of CNVs was done using ddPCR as previously described (Ceyhan‐Birsoy et al, ).…”