Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families.

EDITOR--Mutations in GJB2, the connexin 26 (Cx26) gene, are thought to account for over 50% of autosomal recessive, non-syndromic, congenital deafness, the most common form of genetic deafness [1 2] and 10-30% of sporadic cases. [2 3] Over 50 recessive mutations in the GJB2 gene have been reported since it was originally described [4] (the connexin 26 (GJB2) deafness homepage at http://www.iro.es/cx26deaf.html). The most common mutation is a deletion of a guanosine nucleotide at position 30-35 (35delG), accounting for approximately 30-63% of mutations in white populations with a carrier frequency of 1:31 in Mediterranean populations. [1 2] However, the 35delG mutation is present at a lower prevalence in different ethnic groups, [5-8] with other mutations occurring at a higher prevalence, such as 167delT in the Jewish population. [9-12] Both the high carrier frequency of GJB2 mutations and the prevalence of non-35delG mutations in non-white populations implies that mutations other than 35delG may be more commo n in non-white ethnic minorities who have settled in the UK, particularly those in which consanguinity is prevalent.

In order to examine strategies suitable for sensitive, medium throughput mutation detection in GJB2, we used denaturing high performance liquid chromatography (DHPLC) to screen for mutations in a cohort of 51 multi-ethnic patients with non-syndromic deafness who presented at our centre for genetic counselling. We found that DHPLC detected all the control mutations in the sample and that no mutations were identified by sequencing that were not detected by DHPLC. Three mutations, W24X, W77X, and Q124X, found in Indian, Pakistani, and Bangladeshi families in this study, have been previously observed in families from the Indian subcontinent, suggesting that they may be common mutations in these ethnic groups.

Methods and results

Fifty one subjects with non-syndromic hearing loss were ascertained through genetic counselling and audiological medicine clinics at Great Ormond Street Hospital, London and from referrals for GJB2 testing to the North Thames (East) Regional Diagnostic Laboratory, London. The ethnic background of the cases was approximately 75% white, but included cases from the Indian subcontinent, such as India, Pakistan, and Sri Lanka. The 51 cases included the unaffected parents of a deaf child who was initially unavailable for mutation testing. Twelve of the cases had previously identified base changes and were used as positive controls (table 1) and 18 of the remainder had already been tested for the 35delG mutation. All cases had congenital sensorineural hearing loss (mostly severe to profound) and were examined by a clinical geneticist to exclude syndromic causes of deafness.

Two sets of primers were used for amplification of the entire coding region, and the GJB2 sequence was taken from GenEmbl accession number M86849. Two …