title: Next generation sequencing-based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory for Molecular MedicinePartners HealthCare Personalized MedicineCambridgeMassachusetts; Department of PathologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusetts.
authors.forename: Ozge
authors.initials: O
authors.lastname: Ceyhan-Birsoy
authors.affiliation: Department of Medical Biophysics Princess Margaret Cancer Centre University Health Network University of Toronto Toronto Ontario Canada.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine Cambridge Massachusetts.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Bowser
authors.affiliation: Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine Cambridge Massachusetts.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hynes
authors.affiliation: Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine Cambridge Massachusetts.
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Frisella
authors.affiliation: Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine Cambridge Massachusetts.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahanta
authors.affiliation: Laboratory for Molecular MedicinePartners HealthCare Personalized MedicineCambridgeMassachusetts; Department of PathologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusetts.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Lebo
authors.affiliation: Laboratory for Molecular MedicinePartners HealthCare Personalized MedicineCambridgeMassachusetts; Department of PathologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusetts.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Amr
authors.affiliation: Laboratory for Molecular MedicinePartners HealthCare Personalized MedicineCambridgeMassachusetts; Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusetts.
authors.forename: Birgit H
authors.initials: BH
authors.lastname: Funke
keywords: Cardiomyopathies; DNA copy number variants; genetic heterogeneity; molecular diagnostics; next‐generation sequencing