Prelingual Deafness: High Prevalence of a 30delG Mutation in the Connexin 26 Gene

Abstract

Prelingual non-syndromic (isolated) deafness is the most frequent hereditary sensory defect. In >80% of the cases, the mode of transmission is autosomal recessive. To date, 14 loci have been identified for the recessive forms (DFNB loci). For two of them, DFNB1 and DFNB2, the genes responsible have been characterized; they encode connexin 26 and myosin VIIA, respectively. In order to evaluate the extent to which the connexin 26 gene (Cx26) contributes to prelingual deafness, we searched for mutations in this gene in 65 affected Caucasian families originating from various countries, mainly tunisia, France, New Zealand and the UK. Six of these families are consanguineous, and deafness was shown to be linked to the DFNB1 locus, 10 are small non consanguineous families in which the segregation of the trait has been found to be compatible with the involvement of DFNB1, and in the remaining 49 families no linkage analysis has been performed. A total of 62 mutant alleles in 39 families were identified. Therefore, mutations in Cx26 represent a major cause of recessively inherited prelingual deafness since according to the present results they would underlie approximately half of the cases. In addition, one specific mutation, 30delG, accounts for the majority (approximately 70%) of the Cx26 mutant alleles. It is therefore one of the most frequent disease mutations so far identified. Several lines of evidence indicate that the high prevalence of the 30delG mutation arises from a mutation hot spot rather than from a founder effect. Genetic counseling for prelingual deafness has been so far considerably impaired by the difficulty in distinguishing genetic and non genetic deafness in families presenting with a single deaf child. Based on the results presented here, the development of a simple molecular test could be designed which should be of considerable help.

Methodology of a multistate study of congenital hearing loss: Preliminary data from Utah newborn screening

“…Approximately 12% of these individuals were identified as having mutations in the GJB2 gene responsible for the hearing loss. This frequency is lower than previously reported frequencies, suggesting a unique population, small numbers, or that the frequency in newborn samples may be lower because the study included milder cases [Denoyelle et al, 1997;Zelante et al, 1997]. The discrepancy in frequency of GJB2 mutations in these studies underscores the need for further study and proper classification of cases.…”

“…To date, 79 loci for nonsyndromic hearing loss have been identified: 40 autosomal dominant, 34 autosomal recessive, and 5 X-linked [Hereditary Hearing Loss Homepage, 2003]. Multiple studies have shown that mutations in the single GJB2 gene may account for up to 50% of nonsyndromic sensorineural autosomal recessive hearing loss or 20% of all childhood hearing loss [Denoyelle et al, 1997;Zelante et al, 1997;Cohn et al, 1999;Green et al, 2002]. The GJB2 gene encodes the connexin 26 protein, which is involved in gap junction formation allowing cell-to-cell diffusion and the transfer of ions between neighboring cells.…”

“…The GJB2 gene encodes the connexin 26 protein, which is involved in gap junction formation allowing cell-to-cell diffusion and the transfer of ions between neighboring cells. The 35delG mutation (previously described as the 30delG mutation) accounts for the majority ($70%) of the GJB2 mutant alleles in Caucasians [Denoyelle et al, 1997;Zelante et al, 1997], contributing significantly to autosomal recessive congenital hearing loss. Based on an extensive review of the literature on the frequency of GJB2 mutations in different populations, Kenneson et al [2002] estimated the carrier frequency of the 35delG mutation in the Caucasian, Northern European population as being 1-3%.…”

Whole-exome sequencing reveals diverse modes of inheritance in sporadic mild to moderate sensorineural hearing loss in a pediatric population

“…The most frequent mode of inheritance of nonsyndromic hearing loss is autosomal recessive (AR) (75-80% of cases). [2][3][4] AR nonsyndromic hearing loss (OMIM 220700) typically has a congenital or prelingual onset. 4 The degree of AR nonsyndromic hearing loss is usually severe or profound, although varying degrees of residual hearing can be observed in a subset of patients.…”

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…Nonsyndromic forms are grouped in autosomal dominant (DFNA), autosomal recessive (DFNB), X‐linked (DNFX) and mitrochondrial subtypes. The most commonly affected gene causing nonsyndromic hearing loss (both in autosomal recessive DFNB1A [MIM 220290] and in autosomal dominant DFNA3A [MIM 601544]) is gap junction beta 2 ( GJB2 , [MIM 121011]), the gene encoding the connexin 26 protein (CX26) (Kelsell et al, 1997; Denoyelle et al, 1997). Depending on the studied population, 20–50% of all recessive nonsyndromic SNHL cases can be attributed to a mutation in GJB2 (Hilgert et al, 2009a; Linden Phillips et al, 2013).…”