Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

Article metrics

Abstract

Purpose

Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.

Methods

The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case–control statistical analyses were performed.

Results

The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.

Conclusion

Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Wang NK, Chiang JPW. Increasing evidence of combinatory variant effects calls for revised classification of low-penetrance alleles. Genet Med. 2018 Nov 2; https://doi.org/10.1038/s41436-018-0347-3 [Epub ahead of print].

  2. 2.

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.

  3. 3.

    Oza AM, DiStefano MT, Hemphill SE, et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat. 2018;39:1593–1613.

  4. 4.

    Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387:80–83.

  5. 5.

    Scott DA, Kraft ML, Carmi R, et al. Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. Hum Mutat. 1998;11:387–394.

  6. 6.

    Scott DA, Kraft ML, Stone EM, et al. Connexin mutations and hearing loss. Nature. 1998;391:32.

  7. 7.

    Wilcox SA, Saunders K, Osborn AH, et al. High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet. 2000;106:399–405.

  8. 8.

    Houseman MJ, Ellis LA, Pagnamenta A, et al. Genetic analysis of the connexin-26 M34T variant: identification of genotype M34T/M34T segregating with mild-moderate non-syndromic sensorineural hearing loss. J Med Genet. 2001;38:20–25.

  9. 9.

    Cucci RA, Prasad S, Kelley PM, et al. The M34T allele variant of connexin 26. Genet Test. 2000;4:335–344.

  10. 10.

    Kelley PM, Harris DJ, Comer BC, et al. Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet. 1998;62:792–799.

  11. 11.

    Abe S, Usami S, Shinkawa H, et al. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet. 2000;37:41–43.

  12. 12.

    Griffith AJ, Chowdhry AA, Kurima K, et al. Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet. 2000;67:745–749.

  13. 13.

    Feldmann D, Denoyelle F, Loundon N, et al. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet. 2004;12:279–284.

  14. 14.

    Pollak A, Skorka A, Mueller-Malesinska M, et al. M34T and V37I mutations in GJB2 associated hearing impairment: evidence for pathogenicity and reduced penetrance. Am J Med Genet A. 2007;143A:2534–2543.

  15. 15.

    Wu CC, Tsai CH, Hung CC, et al. Newborn genetic screening for hearing impairment: a population-based longitudinal study. Genet Med. 2017;19:6–12.

  16. 16.

    Chai Y, Chen D, Sun L, et al. The homozygous p.V37I variant of GJB2 is associated with diverse hearing phenotypes. Clin Genet. 2015;87:350–355.

  17. 17.

    White TW, Deans MR, Kelsell DP, Paul DL. Connexin mutations in deafness. Nature. 1998;394:630–631.

  18. 18.

    Skerrett IM, Di WL, Kasperek EM, et al. Aberrant gating, but a normal expression pattern, underlies the recessive phenotype of the deafness mutant Connexin26M34T. FASEB J. 2004;18:860–862.

  19. 19.

    Palmada M, Schmalisch K, Bohmer C, et al. Loss of function mutations of the GJB2 gene detected in patients with DFNB1-associated hearing impairment. Neurobiol Dis. 2006;22:112–118.

  20. 20.

    Martin PE, Coleman SL, Casalotti SO, et al. Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness. Hum Mol Genet. 1999;8:2369–2376.

  21. 21.

    Thonnissen E, Rabionet R, Arbones ML, et al. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002;111:190–197.

  22. 22.

    Bicego M, Beltramello M, Melchionda S, et al. Pathogenetic role of the deafness-related M34T mutation of Cx26. Hum Mol Genet. 2006;15:2569–2587.

  23. 23.

    Zonta F, Buratto D, Cassini C, et al. Molecular dynamics simulations highlight structural and functional alterations in deafness-related M34T mutation of connexin 26. Front Physiol. 2014;5:85.

  24. 24.

    D’Andrea P, Veronesi V, Bicego M, et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002;296:685–691.

  25. 25.

    de Wolf E, van de Wiel J, Cook J, Dale N Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro. Physiol Rep. 2016;4:e13038;1–12.

  26. 26.

    Maeda S, Nakagawa S, Suga M, et al. Structure of the connexin 26 gap junction channel at 3.5 A resolution. Nature. 2009;458:597–602.

  27. 27.

    Yilmaz A. Bioinformatic analysis of GJB2 gene missense mutations. Cell Biochem Biophys. 2015;71:1623–1642.

  28. 28.

    Bruzzone R, Veronesi V, Gomes D, et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003;533:79–88.

  29. 29.

    Kim J, Jung J, Lee MG, et al. Non-syndromic hearing loss caused by the dominant cis mutation R75Q with the recessive mutation V37I of the GJB2 (Connexin 26) gene. Exp Mol Med. 2015;47:e169.

  30. 30.

    Chen Y, Hu L, Wang X, et al. Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2. Sci Rep. 2016;6:33279.

  31. 31.

    Chan DK, Chang KW. GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope. 2014;124:E34–53.

  32. 32.

    Lameiras AR, Goncalves AC, Santos R, et al. The controversial p.Met34Thr variant in GJB2 gene: two siblings, one genotype, two phenotypes. Int J Pediatr Otorhinolaryngol. 2015;79:1316–1319.

  33. 33.

    Dai ZY, Sun BC, Huang SS, et al. Correlation analysis of phenotype and genotype of GJB2 in patients with non-syndromic hearing loss in China. Gene. 2015;570:272–276.

  34. 34.

    Chen K, Sun L, Zong L, et al. GJB2 and mitochondrial 12S rRNA susceptibility mutations in sudden deafness. Eur Arch Otorhinolaryngol. 2016;273:1393–1398.

  35. 35.

    Lim LH, Bradshaw JK, Guo Y, et al. Genotypic and phenotypic correlations of DFNB1-related hearing impairment in the Midwestern United States. Arch Otolaryngol Head Neck Surg. 2003;129:836–840.

  36. 36.

    Lee KH, Larson DA, Shott G, et al. Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations. Laryngoscope. 2009;119:554–558.

  37. 37.

    Kenna MA, Feldman HA, Neault MW, et al. Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss. Arch Otolaryngol Head Neck Surg. 2010;136:81–87.

  38. 38.

    Jiang Y, Huang S, Deng T, et al. Mutation spectrum of common deafness-causing genes in patients with non-syndromic deafness in the Xiamen Area, China. PLoS ONE. 2015;10:e0135088.

  39. 39.

    Zoll B, Petersen L, Lange K, et al. Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10. Hum Mutat. 2003;21:98.

Download references

Acknowledgements

We thank members of the ClinGen Hearing Loss Working Group who participated in the discussion on applying ACMG/AMP and HL-specific rules to determine the classification of the p.Met34Thr and p.Val37Ile variants. We thank Donglin Bai of the Schulich School of Medicine & Dentistry, Western University for critical and constructive comments on the manuscript. This work was supported by National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) grants R03DC013866 and R01DC015052 (to J.S.); R01DC011835 (to K.B.A.); NIH/NINDS R01AR059049, NIH/National Human Genome Research Institute (NHGRI) U01HG008666. and three other intramural grants (to K.Z.); a Grant-in-Aid for Clinical Research from the National Hospital Organization H27-NHOkankaku-02, Japan (to T.M.); Spanish Instituto de Salud Carlos III grants PI14/01162 (to I.d.C.) and PI14/0948 (to M.A.M.-P.); Regional Government of Madrid-Spain RAREGENOMICS-CAM grant B2017/BMD3721 (to M.A.M.-P.); and Plan Estatal de I+D+I 2013–2016 with cofunding from the European Regional Development Fund (to I.d.C. and M.A.M.-P.).

ClinGen Hearing Loss Working Group

Hela Azaiez32, Kevin T. Booth32, Richard J. Smith32, Anne B. Giersch33, Cynthia C. Morton33, Xue Z. Liu34, Mustafa Tekin34, Yu Lu35, Huijun Yuan35, Hideki Mutai36, Lisa Schimmenti37

Author information

Correspondence to Jun Shen PhD, FACMG or Ahmad N. Abou Tayoun PhD, FACMG.

Ethics declarations

Disclosure

J.S., A.M.O., H.D., J.J.A., M.L., K.Z., S.S.A., H.L.R., and A.N.A.T. worked for pay for service diagnostic laboratories providing genetic testing. H.P.K., S.G., R.M.-H., K.M., N.N., and A.W. worked for commercial laboratories providing genetic testing. The other authors declare no conflicts of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Keywords

  • ClinGen
  • hearing loss
  • incomplete penetrance
  • variant classification
  • variant interpretation

Further reading