Реконструкция гаплотипа-основателя с мутацией c.644G>A p.(Trp215*) гена CLIC5, приводящей к ювенильной аутосомно-рецессивной глухоте (DFNB103) в Якутии

Earlier, in Yakutia, using whole exome sequencing (WES) the genetic cause of juvenile autosomal recessive deafness (DFNB103, OMIM 616042), caused by the nonsense variant c.644G>A p.(Trp215*) of the CLIC5 gene, was identified. This work presents the results of the analysis of the carrier frequency of the variant c.644G>A p.(Trp215*) in 512 adult individuals without hearing impairment from 8 populations of Eastern Siberia (Russians, Russian old-timers, Yakuts, Evenks, Evens, Dolgans, Yukaghirs and Chukchi). With the highest carrier frequency this mutation was found in the Yukaghir population (3.2%), with intermediate carrier frequencies in Evens (1.4%) and Evenks (1.4%), with the lowest carrier frequency in Yakuts (0.8%) and was absent in Russians (including Russian old-timers), Dolgans and Chukchi. The analysis of haplotypes obtained as a result of genotyping of ~ 730,000 SNP-markers was carried out in 18 patients of various ethnic origins (Evens, Evenks, and Yakuts) homozygous for the c.644G>A p.(Trp215*) mutation, and 83 individuals without this mutation. All 18 individuals with the homozygous variant c.644G>A p.(Trp215*) showed homozygosity blocks of different lengths on chromosome 6, which were absent in the control group. All blocks overlapped in one region, 785.5 kb in length (224 SNP), which is evidence in favor of a single origin of the c.644G>A p.(Trp215*) mutation. Estimation of the age of c.644G>A-haplotypes showed that the expansion of mutant chromosomes could begin in the Late Neolith period (Bronze or Early Iron Age), and most likely not in the Turkic peoples, but in the Tungus-speaking, Ural-speaking, or even in paleoasians peoples. The data obtained indicate the relevance of the targeted analysis of the c.644G>A p. (Trp215*) mutation of the CLIC5 gene in the target groups of patients, among the indigenous population of Siberia and East Asia, and possibly among the populations of the Arctic coast of Eurasia and North America.