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In the course of previous investigations carried out in the Republic of Sakha (Yakutiya), we have identified the main molecular-genetic factor responsible for the hereditary impairment of hearing among the indigenous population (mostly the Yakuts).The disease was shown to be attributable to the c.-23+1G>A mutation localized in the splice donor site (exon 1) of the GJB2 (Cx26) gene. The present study involved the comprehensive audiological analysis of the patients homozygous for the c.-23+1G>A mutation in the GJB2 gene based on the results of the study of a large sample of the patients residing in Yakutiya. All individuals with the GJB2 genotype c.-23+1G>A/c.-23-1G>A (n=108) at the mean age of 14.32±4.7 years (all ethnic Yakuts)were examined with the use oftonal threshold audiometry for air conduction testing at the frequencies of 0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and bone conduction testing at the frequencies of 0.25, 0.5, 1.0, and 4.0 with a step of 5.0 dB.The results of the ASSR test were used whenever tonal threshold audiometry proved impracticable The data obtained in the study characterize the allelic form of the disease associated with the GJB2 genotype c.-23+1G>A/c.-23-1G>A as the congenital bilateral symmetric (90.1%), sensorineural (90.1%) form of hearing impairment of variable severity (from grade 1 to complete deafness) with the «flat» audiological profile (median slope not more than 5.0 dB in the extended frequency range (EFR) of 0.5, 1.0, 2.0, and 4.0, kHz). It is concluded that the results of the audiological analysis performed in the present study give evidence of relatively homogeneous but variable in terms of severity impairment of hearing in the patients homozygous for the c.-23+1G>A mutation in the GJB2 (Cx26) gene. It may serve as a positive prognostic sign to be used in the development and prescription of hearing aids.

The c.-23+1G>A splice site mutation is one of the most frequent mutations of gene GJB2 (Cx26, 13q11-q12) associated with congenital non-syndromic autosomal recessive deafness. This mutation is characterized by a wide spread from Eastern Siberia and Central Asia to Eastern Europe, the Middle East, and South Asia. It is currently unknown whether this mutation spread over such a vast territory as a result of the founder effect or there were several local centers of origin of this mutation. For the first time, on the basis of the analysis of variability of nine SNP markers, five different haplotypes in deaf patients homozygous for mutation c.-23+1G>A from six Eurasian populations were reconstructed. The structure of the haplotypes revealed in Yakuts, Russians, Evenks, Tuvinians, Mongols, and Turks makes it possible to assume that mutation c.-23+1G>A ( GJB2) could have spread across Eurasia as a result of the founder effect. The greatest diversity of haplotypes with c.-23+1G>A was found in patients from Mongolia, which probably refers to the earlier period of expansion of haplotypes carrying this mutation on the territory of Central Asia. [ABSTRACT FROM AUTHOR]