title: Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.
abstract: Hearing loss is the most common sensory deficit in humans, affecting 1 in 500 newborns. Due to its genetic heterogeneity, comprehensive diagnostic testing has not previously been completed in a large multiethnic cohort. To determine the aggregate contribution inheritance makes to non-syndromic hearing loss, we performed comprehensive clinical genetic testing with targeted genomic enrichment and massively parallel sequencing on 1119 sequentially accrued patients. No patient was excluded based on phenotype, inheritance or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 patients (39%). Pathogenic variants were found in 49 genes and included missense variants (49%), large copy number changes (18%), small insertions and deletions (18%), nonsense variants (8%), splice-site alterations (6%), and promoter variants (<1%). The diagnostic rate varied considerably based on phenotype and was highest for patients with a positive family history of hearing loss or when the loss was congenital and symmetric. The spectrum of implicated genes showed wide ethnic variability. These findings support the more efficient utilization of medical resources through the development of evidence-based algorithms for the diagnosis of hearing loss.
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.|Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, 52242, IA, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Sloan-Heggen
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Amanda O
authors.initials: AO
authors.lastname: Bierer
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: A Eliot
authors.initials: AE
authors.lastname: Shearer
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Kolbe
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Nishimura
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Frees
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Sean S
authors.initials: SS
authors.lastname: Ephraim
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Seiji B
authors.initials: SB
authors.lastname: Shibata
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Booth
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Campbell
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Ranum
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Weaver
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: E Ann
authors.initials: EA
authors.lastname: Black-Ziegelbein
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA.
authors.forename: Hela
authors.initials: H
authors.lastname: Azaiez
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA, 52242, USA. richard-smith@uiowa.edu.|Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, 52242, IA, USA. richard-smith@uiowa.edu.|Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, 52242, IA, USA. richard-smith@uiowa.edu.
authors.forename: Richard J H
authors.initials: RJH
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male