title: Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran.
abstract: BACKGROUND
  Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes.
  
  
  METHODS
  Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families.
  
  
  RESULTS
  We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations.
  
  
  CONCLUSIONS
  This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Sloan-Heggen
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Babanejad
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Beheshtian
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Simpson
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Booth
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Fariba
authors.initials: F
authors.lastname: Ardalani
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Frees
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Marzieh
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Mozafari
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Mehrjoo
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Jamali
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Saeideh
authors.initials: S
authors.lastname: Vaziri
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Tara
authors.initials: T
authors.lastname: Akhtarkhavari
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Niloofar
authors.initials: N
authors.lastname: Bazazzadegan
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Nooshin
authors.initials: N
authors.lastname: Nikzat
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Arzhangi
authors.affiliation: Genetics Counseling Center, Kerman Welfare Institution, Kerman, Iran.
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Sabbagh
authors.affiliation: Division of Pediatric Nephrology, Hazrat-e-Ali Asghar Educational & Treatment Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Hasan
authors.initials: H
authors.lastname: Otukesh
authors.affiliation: Meybod Genetics Research Center, Shahid Fiazbakhsh Rehabilitation Comprehensive Center, Welfare Organization, Yazd, Iran.
authors.forename: Seyed Morteza
authors.initials: SM
authors.lastname: Seifati
authors.affiliation: Meybod Genetics Research Center, Shahid Fiazbakhsh Rehabilitation Comprehensive Center, Welfare Organization, Yazd, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khodaei
authors.affiliation: Genetic Counseling Center, Shiraz Welfare Institution, Shiraz, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Taghdiri
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Meyer
authors.affiliation: Head and Neck Surgery Department and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Daneshi
authors.affiliation: Head and Neck Surgery Department and Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Farhadi
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA Interdepartmental PhD Program in Genetics, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Molecular Otolaryngology & Renal Research Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Hela
authors.initials: H
authors.lastname: Azaiez
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
mesh_terms: D000072259:Connexin 26; D017630:Connexins; D003241:Consanguinity; D018703:Founder Effect; D005787:Gene Frequency; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D034381:Hearing Loss / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007492:Iran
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26
keywords: Copy-number; Diagnostics tests; Molecular genetics; Neurosciences