Spectrum and frequency of GJB2 (Cx26) gene mutations in patients with hearing impairments in the Republic of Buryatia

In the diagnosis of hereditary non-syndromic hearing loss (HL), the methods of molecular genetic analysis of the GJB2 (Cx26) gene mutations provide high valuable information. For the first time, in the Republic of Buryatia (Eastern Siberia), the spectrum and frequency of GJB2 gene mutations were determined in a sample of 165 individuals with HL using sequencing of significant regions of the GJB2 gene. A total of 13 known allelic variants were found (c.-254C>T, c.-49G>A, c.-23+1G>A, c.35delG, c.79G>A, c.101T>C, c.109G>A, c.235delC, c.299_300delAT, c.327_328delinsA, c.341A>G, c.457G>A u c.516G>C). In the sample of Buryat patients, the mutation spectrum was represented by five GJB2 variants: c.-23+1G>A (4.1%), c.109G>A (0.6%), c.235delC (1.4%), c.327_328delGGinsA (0.6%), c.516G>C (0.6%). Five mutations were found among Russian patients: c.35delG (25.7%), c.-23+1G>A (3.3%), c.109G>A (1.9%), c.101T>C (0.6%), c.299_300delAT (0.6%). In general, the contribution of biallelic mutations of the GJB2 gene to the etiology of HL in the total sample of patients in Buryatia was 15.8% (26/165). When the total sample of patients was divided by ethnicity the contribution of biallelic mutations of the GJB2 gene to the etiology of HL in Buryat patients was 5.1% (4/79), and in Russian patients - 28.9% (22/76). Thus, the results of our study indicate that the mutations in the GJB2 gene are not the main cause of HL in Buryats. Probably, in some GJB2-negative patients (84.2% in our study), HL may be due to the mutations in other genes responsible for the development of hereditary hearing impairments.

deafness, mutations of the GJB2 (Cx26) gene, Republic of Buryatia, autosomal recessive 1A

1. 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.

2. Tsukada K., Nishio S.Y., Hattori M., Usami S. Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review. Ann Otol Rhinol Laryngol 2015; 124. (Suppl): 61-76. doi: 10.1177/0003489415575060.

3. Hamelmann C., Amedofu G.K., Albrecht K. et al. Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum. Mutat 2001; 18(1): 84-85.

4. Brownstein Z., Avraham K.B. Deafness genes in Israel: implications for diagnostics in the clinic. Pediatr Res 2009; 66(2): 128-34. doi: 10.1203/PDR.0b013e3181aabd7f.

5. Tamayo M.L., Olarte M., Gelvez N. et al. Molecular studies in the GJB2 gene (Cx26) among a deaf population from Bogota, Colombia: results of a screening program. Int J Pediatr Otorhinolaryngol 2009; 73(1): 97-101.

6. Paz-y-Miño C., Beaty D., López-Cortés A., Proaño I. Frequency of GJB2 and del(GJB6-D13S1830) mutations among an Ecuadorian mestizo population. Int J Pediatr Otorhinolaryngol 2014; 78(10): 1648-1654. doi: 10.1016/j.ijporl.2014.07.014.

7. Carranza C., Menendez I., Herrera M. et al. Mayan founder mutation is a common cause of deafness in Guatemala. Clin Genet 2016; 89: 461-465. doi: 10.1111/cge.12676.

8. Posukh O., Pallares-Ruiz N., Tadinova V. et al. First molecular screening of deafness in the Altai Republic population. BMC Med. Genet 2005; 6(1): 12.

9. 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. J Hum Genet 2011; 56(9): 631-639. doi: 10.1038/jhg.2011.72.

10. Barashkov N.A., Pshennikova V.G., Posukh O.L. et al. Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic). PLoS One 2016; 11(5): e0156300. doi: 10.1371/journal.pone.0156300.

11. Бады-Хоо М.С., Бондарь А.А., Морозов И.В. и др. Изучение наследственных форм тугоухости / глухоты в Республике Тыва. Сообщение II. Оценка спектра мутаций в гене GJB2 (Сx26) и их вклада в этиологию потери слуха. Медицинская генетика 2014; 13(11): 23-33.

12. Posukh O.L., Zytsar M.V., Bady-Khoo M.S. et al. Unique mutational spectrum of the GJB2 Gene and its pathogenic contribution to deafness in Tuvinians (Southern Siberia, Russia): A high prevalence of rare variant c.516G>C (p.Trp172Cys). Genes 2019; 10(6): 429. doi: 10.3390/genes10060429.

13. Пшенникова В.Г., Терютин Ф.М., Барашков Н.А. и др. Клинико-аудиологический и генеалогический анализ случаев нарушения слуха в Республике Бурятия. Якутский медицинский журнал 2020; 4(72): 44-49. doi: 10.25789/YMJ.2020.72.12.

14. 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. J. Genet 2006; 85(3): 213-216.

15. Zelante L., Gasparini P., Estivill X. et al. Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum. Mol. Genet 1997; 6(9): 1605-1609.

16. 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. Am. J. Hum. Genet 1998; 62(4): 792-799.

17. Green G.E., Cunniff C. Genetic evaluation and counseling for congenital deafness. Adv. Otorhinolaryngol 2002; 61: 230-240. doi: 10.1159/000066814.

18. Tang H.Y., Fang P., Ward P.A. et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impairedcases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A 2006; 140(22): 2401-2415.

19. Tekin M., Xia X.J., Erdenetungalag R. et al. GJB2 mutations in Mongolia: complex alleles, low frequency, and reduced fitness of the deaf. Ann. Hum. Genet 2010; 74(2): 155-64.

20. Choi S-Y., Lee K.Y., Kim H-J. et al. Functional evaluation of GJB2 variants in nonsyndromic hearing loss. Mol. Med 2011; 17(5-6): 550-556. doi: 10.2119/molmed.2010.00183.

21. Zytsar M.V., Bady-Khoo M.S., Danilchenko V.Y. et al. High Rates of Three Common GJB2 Mutations c.516G>C, c.-23+1G>A, c.235delC in Deaf Patients from Southern Siberia Are Due to the Founder Effect. Genes (Basel) 2020; 11(7): 833. doi: 10.3390/genes11070833.

22. Davoudi-Dehaghani E., Fallah M-S., Shirzad T. et al. Reporting the presence of three different diseases causing GJB2 mutations in a consanguineous deaf family. Int J Audiol 2014; 53(2): 128-31. doi: 10.3109/14992027.2013.850748.

23. Близнец Е.А., Галкина В.А., Матющенко Г.Н. и др. Изменения в гене коннексина 26 - GJB2 - при нарушениях слуха у российских пациентов: результаты многолетней молекулярной диагностики наследственной несиндромальной тугоухости. Генетика 2012; 48(1): 112-124.

24. Dai P., Yu F., Han B. et al. GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J. Transl. Med 2009; 14: 7-26. doi: 10.1186/1479-5876-7-26.

25. Liu Q.M., Tian Y., Yu J.J. et al. [A follow-up study of abnormal mutation in neonatal deafness gene screening]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2019; 54(12): 881-887. doi: 10.3760/cma.j.issn.1673-0860.2019.12.001. (In Chinese).