Analysis of hearing thresholds in patients with hearing impairments associated with mutations of the GJB2 gene (Sh26) in Buryatia

In this work, the hearing analysis of 26 patients with hearing impairment, who had biallelic mutations of the GJB2 gene (Sh26) was carried out in the Republic of Buryatia. Genotype-phenotypic comparisons showed that for all 7 GJB2 genotypes: c.[35delG];[35delG]; c.[-23+1G>A];[35delG]; c.[-23+1G>A];[-23+1G>A]; c.[-23+1G>A];[516G>C]; c.[-23+1G>A];[327_328delGGinsA]; c.[35delC];[299_300delAT]; c.[235delC];[235delC] congenital (detected before one year – 76.0%), symmetrical (84.6%), sensorineural (100.0%) form of hearing loss are detected, variable in severity both between different GJB2 genotypes and within the same GJB2 genotype (grade III in 9.6%, grade IV in 17.3%, deafness in 73.1%). Based on the median hearing thresholds PTA_{0.5,1.0,2.0,4.0 kHz,} three phenotypes were identified - "mild phenotype", "medium phenotype" and "severe phenotype". We conducted a genotype-phenotypic comparison, as a result of which GJB2-genotypes c.[-23+1G>A];[-23+1G>A] and c.[-23+1G>A];[516G>C] were assigned to genotypes with “average” (median 66.875 dB and 64.375 dB, respectively), and the remaining GJB2-genotypes: c.[35delG];[35delG]; c.[-23+1G>A];[35delG]; c.[-23+1G>A];[327_328delGGinsA]; c.[35delC];[299_300delAT]; c.[235delC];[235delC] - to genotypes with a "severe" form of the phenotypic effect. No genotypes with a "mild" phenotypic effect have been identified. At the same time, the hearing thresholds for GJB2 genotypes with the "average" form of the phenotypic effect (c.[-23+1G>A(;)-23+1G>A] and c.[-23+1G>A(;)516G>C]) were significantly better (p=0.02268) than in the reference group with GJB2 genotype с.[35delG];[35delG].

1. Teryutin F.M., Barashkov N.A., Kunelskaya N.L. [et al.] Audiologicheskij analiz u pacientov s poterej sluha, gomozigotnyh po mutacii s.23+1G>A gena GJB2 v YAkutii [Audiological analysis in patients with hearing loss homozygous for the c.-23+1G>A mutation of the GJB2 gene in Yakutia]. Vestnik otorinolaringologii [Bulletin of Otorhinolaryngology. 2016; 81 (1): 19-24 (In Russ.).] doi:10.17116/otorino201681119-24

2. Pshennikova V.G., Cherdonova A.M., Teryutin F.M. [et al.] Spektr i chastota mutacij gena GJB2 (Skh26) u pacientov s narusheniyami sluha v Respublike Buryatiya [Spectrum and frequency of mutations in the GJB2 (Cx26) gene in patients with hearing impairment in the Republic of Buryatia]. Medicinskaya genetika [Medical genetics. 2021;20(7):26-36 (In Russ.).] https://doi.org/10.25557/2073-7998.2021.07.26-36

3. Cryns K., Orzan E., Murgia A. [et al] A genotype-phenotype correlation for GJB2 (connexin 26) deafness. Journal of Medical Genetics. 2004 4;41(3):147-154. doi: 10.1136/jmg.2003.013896.

4. Barashkov N.A., Dzhemileva L.U., Fedorova S.A. [et al]. Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect. Journal of Human Genetics. 2011;56(9):631-639. doi: 10.1038/jhg.2011.72.

5. Chan, D.K., Chang, K.W. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope. 2014; 124(2): E34-53. doi: 10.1002/lary.24332.

6. Oguchi T., Ohtsuka A, Hashimoto S. [et al]. Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns. J Hum Genet. 2005;50(2):76-83. doi: 10.1007/s10038-004-0223-7.

7. Kelsell D.P., Dunlop J., Stevens H.P [et al.] Connexin 26 mutations in hereditary nonsyndromic sensorineural deafness. Nature. 1997;387(6628):80-83. doi: 10.1038/387080a0.

8. Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis / T. Kikuchi, R. Kimura, D. Paul. [et al] // Anatomy and Embryology. 1995. № 2 (191). doi: 10.3109/00016489409126097.

9. Snoeckx R.L., Huygen P.L.M., Feldmann D. [et al]. GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet. 2005 Dec; 77(6): 945–957. Published online 2005 Oct 19. doi: 10.1086/497996

10. Morton, P.C., Nance W.E. Newborn Hearing Screening A Silent Revolution. New England Journal of Medicine. 2006; 20 (354): 2151–2164. doi: 10.1056/NEJMra050700.

11. Kelley P.M., Harris D.J., Comer B.C. [et al] Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. The American Journal of Human Genetics. 1998;62(4):792-799. doi: 10.1086/301807.

12. Hilgert N., Huentelman M.J., Thorburn A.Q. [et al] Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifi gene. European Journal of Human Genetics. 2008;17(4):517-524. doi:10.1038/ejhg.2008.201.

13. Sirmaci, A., Akcayoz-Duman, D., Tekin M. The c.IVS1+1G>A mutation in the GJB2 gene is prevalent and large deletions involving the GJB6 gene are not present in the Turkish population. Journal of Genetics. 2006;85(3):213-216. doi: 10.1007/bf02935334.

14. Bajaj Y., Sirimanna T., Albert D.M. [et al] Spectrum of GJB2 mutations causing deafness in the British Bangladeshi population. Clinical Otolaryngology. 2008;33(4):313-318. doi: 10.1111/j.1749-4486.2008.01754.x.

15. Tsukada, K, Nishio, S, Usami, S. Deafness Gene Study Consortium. A large cohort study of GJB2 mutation in Japanese hearing loss patients. / K. Tsukada // Clinical Genetics. 2010;78(5):464470. doi: 10.1111/j.1399-0004.2010.01407.x.