title: Copy number variants are a common cause of non-syndromic hearing loss.
abstract: BACKGROUND
  Copy number variants (CNVs) are a well-recognized cause of genetic disease; however, methods for their identification are often gene-specific, excluded as 'routine' in screens of genetically heterogeneous disorders, and not implemented in most next-generation sequencing pipelines. For this reason, the contribution of CNVs to non-syndromic hearing loss (NSHL) is most likely under-recognized. We aimed to incorporate a method for CNV identification as part of our standard analysis pipeline and to determine the contribution of CNVs to genetic hearing loss.
  
  
  METHODS
  We used targeted genomic enrichment and massively parallel sequencing to isolate and sequence all exons of all genes known to cause NSHL. We completed testing on 686 patients with hearing loss with no exclusions based on type of hearing loss or any other clinical features. For analysis we used an integrated method for detection of single nucleotide changes, indels and CNVs. CNVs were identified using a previously published method that utilizes median read-depth ratios and a sliding-window approach.
  
  
  RESULTS
  Of 686 patients tested, 15.2% (104) carried at least one CNV within a known deafness gene. Of the 38.9% (267) of individuals for whom we were able to determine a genetic cause of hearing loss, a CNV was implicated in 18.7% (50). We identified CNVs in 16 different genes including 7 genes for which no CNVs have been previously reported. CNVs of STRC were most common (73% of CNVs identified) followed by CNVs of OTOA (13% of CNVs identified).
  
  
  CONCLUSIONS
  CNVs are an important cause of NSHL and their detection must be included in comprehensive genetic testing for hearing loss.
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: A Eliot
authors: AE
authors: Shearer
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA ; Iowa Institute of Human Genetics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors: Diana L
authors: DL
authors: Kolbe
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: Hela
authors: H
authors: Azaiez
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: Christina M
authors: CM
authors: Sloan
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: Kathy L
authors: KL
authors: Frees
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: Amy E
authors: AE
authors: Weaver
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
authors: Erika T
authors: ET
authors: Clark
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA ; Iowa Institute of Human Genetics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors: Carla J
authors: CJ
authors: Nishimura
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA ; Iowa Institute of Human Genetics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
authors: E Ann
authors: EA
authors: Black-Ziegelbein
authors: Department of Otolaryngology - Head and Neck Surgery, Molecular Otolaryngology & Renal Research Labs, University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA ; Iowa Institute of Human Genetics, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA ; Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa 52242, USA.
authors: Richard J H
authors: RJ
authors: Smith