The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia.

Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene. In this study we present the novel truncating variant c.644 G > A p.(Trp215*) of this gene which was found in homozygous state among 22 patients with hearing loss (HL) from 16 unrelated families living in the Sakha Republic of Russia (Eastern Siberia). Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound). Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies. In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age. In average the patients with DFNB103 lost 7.4 ± 13.65 dB on the speech frequency range in pure tone averages (PTA_{0.5,1.0,2.0,4.0 kHz}) per year until reaching profound deafness in the second or third decade of the life. The high frequency of c.644 G > A p.(Trp215*) was found among Siberian GJB2-negative patients (9.9%) and this variant was not detected in GJB2-negative patients of Caucasian descent (predominantly Russians). The haplotype analysis based on the 730,000 whole genome SNP-markers indicates common origin of all studied mutant chromosomes. We conclude that the high prevalence of DFNB103 in Eastern Siberia is the result of founder effect, which occurred ~2500 years ago (~78 generations). These findings expand our knowledge of causative role of pathogenic variants in CLIC5 gene to the etiology of the HL.