Strong linkage disequilibrium for the frequent GJB2 35delG mutation in the Greek population

Abstract

Approximately one in 1,000 children is affected by severe or profound hearing loss at birth or during early childhood (prelingual deafness). Up to 40% of congenital, autosomal recessive, severe to profound hearing impairment cases result from mutations in a single gene, GJB2, that encodes the connexin 26 protein. One specific mutation in this gene, 35delG, accounts for the majority of GJB2 mutations detected in Caucasian populations. Some previous studies have assumed that the high frequency of the 35delG mutation reflects the presence of a mutational hot spot, while other studies support the theory of a common founder. Greece is among the countries with the highest carrier frequency of the 35delG mutation (3.5%), and a recent study raised the hypothesis of the origin of this mutation in ancient Greece. We genotyped 60 Greek deafness patients homozygous for the 35delG mutation for six single nucleotide polymorphisms (SNPs) and two microsatellite markers inside or flanking the GJB2 gene. The allele distribution in the patients was compared to 60 Greek normal hearing controls. A strong linkage disequilibrium was found between the 35delG mutation and markers inside or flanking the GJB2 gene. Furthermore, we found a common haplotype with a previous study, suggesting a common founder for the 35delG mutation.

Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East

“…As haplotype data suggested, it arose from a single mutational event about 10,000 years ago somewhere in the Mediterranean region or in the Middle East. Then it spread throughout Europe along the two Neolithic population movement routes [84-86]. Comparing frequency data of HBB gene mutations such as the c.118C > T (also described as the codon 39 C > T mutation) and c.IVS1-110G>A substitutions within the different parts of the Maghreb region reveals important differences.…”

Carrier frequency of GJB2 gene mutations c.35delG, c.235delC and c.167delT among the populations of Eurasia

“…25 The role of the founder effect in the origin and distribution of several mutations of the GJB2 gene was well established. 7, [26][27][28][29][30] Furthermore, novel hypotheses for the probable specific mechanism (combination of improved genetic fitness and assortative mating) for selective amplification of the commonest form of recessive deafness in the populations and of probable heterozygote advantage of GJB2 recessive mutations have been suggested. 31,32 Data on the mutation spectrum and prevalence of major mutations of the GJB2 gene in various ethnic groups are very important for the development of molecular diagnostics tools for identifying genetic causes of hereditary hearing loss; however, data on the prevalence of major GJB2 mutations in some populations are still not available.…”

BanI/D13S141/D13S175 Represents a Novel Informative Haplotype at the GJB2 Gene Region in the Iranian Population

“…Given the presence of relatively high proportion of informative haplotypes in the population, D 0 and v 2 values for the pairing of these three markers were calculated using the 2LD program (Zhao 2004;Kokotas et al 2008;Feldmann et al 2009). D 0 ranges between 0 and 1.…”

“…LD was measured by using the standardized D 0 first introduced by Lewontin (Lewontin 1964;Raymond and Rousset 1995). D 0 , which is the LD relative to its maximum value for a given set of allelic frequencies for the pair of sites, was calculated using 2LD computer program (Zhao 2004;Kokotas et al 2008;Mahdieha et al 2010). In this sense, D 0 is a 117 normalized value of LD.…”