title: GJB2: the spectrum of deafness-causing allele variants and their phenotype.
abstract: Genetic testing was completed on 1,294 persons with deafness referred to the Molecular Otolaryngology Research Laboratories to establish a diagnosis of DFNB1. Exon 2 of GJB2 was screened for coding sequence allele variants by denaturing high-performance liquid chromatography (DHPLC) complemented by bidirectional sequencing. If two deafness-causing mutations of GJB2 (encoding Connexin 26) were identified, further screening was not performed. If only a single deafness-causing mutation was identified, we screened for the g.1777179_2085947del (hereafter called del(GJB6-D13S1830); GenBank NT_024524.13) and mutations in the noncoding region of GJB2. Phenotype-genotype correlations were evaluated by categorizing mutations as either protein truncating or nontruncating. A total of 205 persons carried two GJB2 exon 2 mutations and were diagnosed as having DFNB1; 100 persons carried only a single deafness-causing allele variant of exon 2. A total of 37 of these persons were c.35delG carriers, and 51 carried other allele variants of GJB2. Persons diagnosed with DFNB1 segregating two truncating/nonsense mutations had a more severe phenotype than persons carrying two missense mutations, with mean hearing impairments being 88 and 37%, respectively (P < 0.05). The number of deaf c.35delG carriers was greater than expected when compared to the c.35delG carrier frequency in normal-hearing controls (P < 0.05), suggesting the existence of at least one other mutation outside the GJB2 coding region that does not complement GJB2 deafness-causing allele variants.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.
authors.forename: Hela
authors.initials: H
authors.lastname: Azaiez
authors.forename: G Parker
authors.initials: GP
authors.lastname: Chamberlin
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Welp
authors.forename: Sai D
authors.initials: SD
authors.lastname: Prasad
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Taggart
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000483:Alleles; D001301:Audiometry, Pure-Tone; D002851:Chromatography, High Pressure Liquid; D000072259:Connexin 26; D017630:Connexins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D004252:DNA Mutational Analysis / Q000379:methods; D003638:Deafness / Q000145:classification / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D005820:Genetic Testing; D005838:Genotype; D006312:Hearing Loss, Bilateral / Q000145:classification / Q000235:genetics*; D006801:Humans; D009154:Mutation; D019683:Penetrance; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26