title: Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations.
abstract: OBJECTIVE
  Despite the identification of mutations in the connexin 26 (GJB2) gene as the most common cause of recessive nonsyndromic hearing loss, the pattern of hearing impairment with these mutations remains inconsistent. Recently a deletion encompassing the GJB6 gene was identified and hypothesized to also contribute to hearing loss. We hereby describe the hearing impairment in Dutch patients with biallelic connexin 26 (GJB2) and GJB2+connexin 30 (GJB6) mutations.
  
  
  METHODS
  The audiograms of patients who were screened for GJB2 and GJB6 mutations were analysed retrospectively. Standard statistical testing was done for symmetry and shape, while repeated measurement analysis was used to assess the relation between mutation and severity. Progression was also studied via linear regression analysis.
  
  
  RESULTS
  Of 222 hearing-impaired individuals, 35 exhibited sequence variations; of these 19 had audiograms for study. Hearing loss in patients with biallelic "radical" (i.e. deletions, nonsense and splice site) mutations was significantly worse than in the wild type and heterozygotes (SAS proc GENMOD, p=0.013). The presence of at least one missense mutation in compound heterozygotes tends to lead to better hearing thresholds compared to biallelic radical mutations (p=0.08). One patient with the [35delG]+[del(GJB6-D13S1830)] genotype was severely impaired. Non-progressive hearing impairment was demonstrated in five 35delG homozygotes in individual longitudinal analyses. However a patient with the [299A>C]+[416G>A] genotype showed significant threshold progression in the lower frequencies. Findings on asymmetry and shape were inconclusive.
  
  
  CONCLUSIONS
  Our data support the hypothesis that severity is a function of genotype and its effect on the amino acid sequence. A bigger cohort is required to establish non-progressivity more definitively.
authors.affiliation: Department of Epidemiology and Biostatistics, Genetic Epidemiology Unit, Erasmus Medical Center Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: Kim P
authors.initials: KP
authors.lastname: van der Donk
authors.forename: Ilse J
authors.initials: IJ
authors.lastname: de Wijs
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Kemperman
authors.forename: Ronald J C
authors.initials: RJ
authors.lastname: Admiraal
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001299:Audiometry; D002648:Child; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009426:Netherlands; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26