Molecular Genetics Applied to Clinical Practice: The Cx26 Hearing Impairment

Abstract

Mutations in the Cx26/GJB2 gene account for a large proportion of pre-lingual hearing impairment with a prevalence up to 50% in autosomal recessive cases and a still undefined prevalence in sporadic cases. Ninety-four subjects affected by non-syndromal sensorineural hearing impairment (NSHI) were enrolled in the study. The patients had either a family history of childhood hearing deficit or represented sporadic cases. The risk of an acquired cause of the deficit has been carefully excluded. Audiological characteristics were investigated. Cx26 mutations were found in 50% of subjects. Seventy-three per cent of mutations in this gene were 35delG, with significant geographical variations. In 7% of the putative Cx26 alleles no mutations were detected either in the coding region or in the non-coding exon 1. Cx26 hearing impairment involves all frequencies, is of variable severity, and is very rarely progressive and most frequently symmetrical between the two ears. The high occurrence of this type of pre-lingual hearing impairment argues for modification of the protocols used to investigate the aetiology of childhood hearing impairment. Early screening for Cx26 mutations in all patients with non-syndromal familial and sporadic permanent childhood hearing impairment seems justified.

Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns

“…There is, however, some controversy regarding genotype/phenotype correlation (Cohn et al 1999;Cryns et al 2004;Denoyelle et al 1999;Estivill et al 1998;Murgia et al 1999;Orzan et al 1999). For example, prediction of the degree of hearing loss was difficult, and environmental factors as well as modifier genes may have been involved (Cohn et al 1999;Murgia et al 1999;Orzan et al 1999). On the other hand, a series of reports have indicated that certain phenotypes are dependent on certain genotypes (Denoyelle et al 1999;Estivill et al 1998).…”

“…It is clear that genetic testing to determine the cause of deafness facilitates prediction of the course of hearing loss and prognostication of language development. There is, however, some controversy regarding genotype/phenotype correlation (Cohn et al 1999;Cryns et al 2004;Denoyelle et al 1999;Estivill et al 1998;Murgia et al 1999;Orzan et al 1999). For example, prediction of the degree of hearing loss was difficult, and environmental factors as well as modifier genes may have been involved (Cohn et al 1999;Murgia et al 1999;Orzan et al 1999).…”

GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review

“…As in the French study discussed above, the 35⌬G homozygotes fell into the moderate or profound range, whereas the compound heterozygotes were dispersed among the three categories (moderate, severe, and profound), suggesting allelic difference in expressivity. 23 Seven additional studies presented data regarding the severity of hearing loss among individuals with GJB2 variants. Because the number of alleles and, therefore, the number of possible genotypes was large, the absolute numbers of cases for each genotype in the studies combined were small.…”

“…Likewise, Orzan et al reported three Italian children with biallelic GJB2 genotypes who had a sudden onset of hearing loss between 18 and 24 months of age, although it is not clear whether prior hearing status was formally documented or based on parental report. 23 Recent research has not focused on rigorous analysis of the possible contribution of GJB2 to postlingual hearing loss. Four published studies have included individuals with postlingual hearing loss.…”

“…In this study, GJB2 variants were detected in 43 of 75 (66%) individuals with symmetrical hearing loss but in only four of the 19 (21%) of those with asymmetrical hearing loss. 23 In the U.K. study, 21 individuals were ascertained through a variety of sources, including otolaryngologists, clinical geneticists, and Deaf associations. The data were presented as average dB difference in hearing loss between the ears: 6.33 (N ϭ 45, SD ϭ 8.09) for GJB2 homozygotes and compound heterozygotes, 6.66 (N ϭ 26, SD ϭ 8.05) for heterozygotes, and 7.86 (N ϭ 175, SD ϭ 11.19) for individuals without GJB2 variations.…”