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

Journal of Human Genetics (2025)Cite this article

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Abstract

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 (PTA0.5,1.0,2.0,4.0 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.

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Acknowledgements

We thank all the patients and blood sample donors who contributed to this study.

Funding

This study was supported by the YSC CMP project “Study of the genetic structure and burden of hereditary pathology of the populations of the Republic of Sakha (Yakutia)” and by the Ministry of Science and Higher Education of the Russian Federation (FSRG-2023-0003).

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Authors and Affiliations

  1. Laboratory of Molecular Genetics, Yakut Science Centre of Complex Medical Problems, str. Yaroslavskogo 6/3, Yakutsk, 677000, Russian Federation

    Vera G. Pshennikova, Fedor M. Teryutin, Alena A. Nikanorova, Sardana A. Fedorova & Nikolay A. Barashkov

  2. Laboratory of Molecular Biology, M.K. Ammosov North-Eastern Federal University, str. Kulakovskogo 46, Yakutsk, 677013, Russian Federation

    Vera G. Pshennikova, Fedor M. Teryutin, Tuyara V. Borisova, Georgii P. Romanov, Alexandra M. Cherdonova, Alena A. Nikanorova, Aisen V. Solovyev, Sardana A. Fedorova & Nikolay A. Barashkov

  3. Novosibirsk State University, str. Pirogova 1, Novosibirsk, 633090, Russian Federation

    Igor V. Morozov

  4. SB RAS Genomics Core Facility, Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, prosp. Lavrentyeva 8, Novosibirsk, 633090, Russian Federation

    Igor V. Morozov & Alexander A. Bondar

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  1. Vera G. Pshennikova
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Contributions

Conducted and designed the experiments and wrote the paper: VGP, FMT, TVB and NAB; Conducted the experiments: GPR, AMC, IVM, AAB and AVS analyzed the data: VGP, FMT, TVB, and AAN; collected the samples: FMT, VGP; discussed and proofed the paper: VGP, FMT, TVB, SAF and NAB.

Corresponding author

Correspondence to Nikolay A. Barashkov.

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The authors declare no competing interests.

Ethical approval

Written informed consent was obtained from all patients participating in the study. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the local Biomedical Ethics Committee at the Yakut Scientific Center of Complex Medical Problems, Yakutsk, Russia (Yakutsk, protocol No. 16 of 16 April 2009).

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Pshennikova, V.G., Teryutin, F.M., Borisova, T.V. et al. The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01406-1

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