A common founder for the 35delG GJB2 gene mutation in connexin 26 hearing impairment

Abstract

Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder eVect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for diVerent single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant diVerences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder. (J Med Genet 2001;38:515-518)

Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese

“…Of the 19 mutations found in Japanese, only five mutations were also found in European populations (Figure 2), further suggesting a founder effect of these mutations as demonstrated in frequent mutations in GJB2. 26,27 In the Caucasoid popula- Pendred A372V 1652insT #12 NSEVA H723R #13 NSEVA 2111ins5bp #14 NSEVA H723R #15 NSEVA N392Y H723R #16 Pendred H723R (homo) #17-P NSEVA S610X S657N #17-M NA S610X #17-A NSEVA S610X (homo) #18 NSEVA -#19 NSEVA -#20 NSEVA H723R #21 NSEVA -#22-P NSEVA IVS7-2A4G H723R #22-S NSEVA IVS7-2A4G H723R #22-F Normal H723R #22-M Normal IVS7-2A4G #23 NSEVA T721M #24-P NSEVA IVS8+1G4A H723R #24-F Normal H723R #24-M Normal IVS8+1G4A #25 NSEVA P123S (hetero) #26 NSEVA IVS7-2A4G H723R #27 NSEVA -#28 NSEVA H723R ( tions, three frequent mutations, L236P (16%), T416P (15%), and IVS8 þ 1G4A (14%), account for nearly half of all PDS mutant alleles. 8 In contrast, these mutations are rare in Japanese (L236P, 0%; T416P, 0%; and IVS8 þ 1G4A, 2%), whereas H723R accounted for 53% of PDS mutations.…”

Non-syndromic recessive deafness in Jordan: mapping of a new locus to chromosome 9q34.3 and prevalence of DFNB1 mutations

“…10 In fact, the 35delG mutation is thought to occur in a hot spot site for mutations, 4,12,13 although a recent article also suggested that its frequency could be secondary to a founder effect. 14 As the number of Jordanian NSRD families linked to the DFNB1 locus was small, testing 108 control chromosomes was necessary to assess the frequency of this mutation in the general Jordanian population. None of these chromosomes bore the 35delG mutation, an indication of its relatively low frequency in this population, which is comparable to its prevalence in some other populations such as African Americans, Asian Americans, Egyptian and English populations.…”

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

“…Among more than 90 different GJB2 mutations, 35delG, accounts for up to 75% of mutated alleles in populations with European ancestry (Estivill et al 1998;Gasparini et al 2000;Van Laer et al 2001). A series of reports has described that patients associated with Fig.…”

“…The status of the 235delC mutation, which seems to be a unique mutation in populations with Asian ancestry, is comparable to the 35delG mutation in Caucasoid populations. High prevalence of 35delG and 235delC mutations in the respective populations are due to a founder effect (Ohtsuka et al 2003;Van Laer et al 2001). Patients homozygous or compound heterozygous for the 235delC mutation exhibit a comparatively severer phenotype (Fig.…”