title: Genotypic and phenotypic correlations of DFNB1-related hearing impairment in the Midwestern United States.
abstract: OBJECTIVE
  To determine the genotypic and phenotypic correlations of hearing impairment (HI) in a midwestern US population related to autosomal recessive nonsyndromic hearing loss locus 1 (DFNB1).
  
  
  METHODS
  A retrospective review.
  
  
  METHODS
  Tertiary care children's hospital.
  
  
  METHODS
  A total of 160 consecutive children diagnosed with idiopathic sensorineural hearing loss.
  
  
  METHODS
  GJB2 genotype and audiometric phenotype.
  
  
  RESULTS
  The prevalence of subjects with HI having biallelic GJB2-related mutations was 15.3% (24/157). Of these 24 patients, 9 (38%) were homozygous 35delG, 6 (25%) had other biallelic nonsense mutations, and 9 (38%) had a missense mutation of at least 1 allele. The allelic prevalence of 35delG was 8.6% (27/314) in the study population and 48% (23/48) in the DFNB1 group. The M34T allele mutation was next most prevalent at 2.2% (7/314) in the study population and 10% (5/48) in the DFNB1 group. Severe to profound HI occurred in 59% of DFNB1 subjects. Genotypes with biallelic nonsense mutations had a high risk of severe to profound HI (88%). DFNB1-related HI was usually bilateral, symmetric, nonprogressive, and had flat audiograms. However, asymmetric HI (22%), sloping audiograms (26%), and even borderline-normal hearing in 1 ear was observed, and these were associated with the presence of at least 1 missense mutation. Two novel mutations, K15T and L90V, were identified. A subject presenting to our clinic with severe to profound HI had a 40% risk of biallelic GJB2 mutation.
  
  
  CONCLUSIONS
  Our population represents a consecutively enrolled clinic population with sensorineural hearing loss. In our DFNB1-related HI cohort, the 35delG mutation and severe to profound HI rates were lower than previously reported. Our missense mutation and M34T allelic prevalence rates were higher than expected and were associated with a less severe hearing loss. The presence of biallelic nonsense mutations was associated with severe to profound hearing loss in nearly 90% of cases. Mild asymmetric HI and sloping audiograms were more often associated with missense mutations.
authors.affiliation: Center for Hearing and Deafness Research, Cincinnati, Ohio, USA.
authors.forename: Lynne H Y
authors.initials: LH
authors.lastname: Lim
authors.forename: John K
authors.initials: JK
authors.lastname: Bradshaw
authors.forename: Yingshi
authors.initials: Y
authors.lastname: Guo
authors.forename: Valentina
authors.initials: V
authors.lastname: Pilipenko
authors.forename: Colm
authors.initials: C
authors.lastname: Madden
authors.forename: David
authors.initials: D
authors.lastname: Ingala
authors.forename: Mehdi
authors.initials: M
authors.lastname: Keddache
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Choo
authors.forename: Richard
authors.initials: R
authors.lastname: Wenstrup
authors.forename: John H
authors.initials: JH
authors.lastname: Greinwald
mesh_terms: D000293:Adolescent; D001301:Audiometry, Pure-Tone; D016009:Chi-Square Distribution; D002648:Child; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D015146:Midwestern United States / Q000453:epidemiology; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D012189:Retrospective Studies
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26