SpringerLink
Log in

A genotype–phenotype correlation in Sicilian patients with GJB2 biallelic mutations

  • Otology
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

The aim of this work was to study the genotype distribution of Sicilian patients with biallelic GJB2 mutations; to correlate genotype classes and/or specific mutations of GJB2 gene (35delG–non-35delG) with audiologic profiles. A total of 10 different mutations and 11 different genotypes were evidenced in 73 SNHL subjects; 35delG (90.36 % of cases) and IVS1+1 (13.69 %) were the most common mutations found in the cohort with a significant difference in the distribution between North and South Sicily. Audiological evaluation revealed a severe (16/73) to profound (47/73) hearing loss (HL) in 86.13 % of cases without significant difference between the degree of HL and the province of origin of the subjects (P = 0.727). The homozygous truncating (T/T) genotype was the most widespread (89.04 % of cases), with a severe-to-profound hearing impairment in 90.36 % of T/T class with respect to truncating/non-truncating (T/NT) and non-truncating/non-truncating (NT/NT) genotypes (P = 0.012). From the comparison of homozygous 35delG and 35delG/non-35delG genotypes, a more profound HL in the homozygous 35delG than in compound heterozygous 35delG/non-35delG (p < 0.0001) resulted. This study confirms that 35delG is the most common mutation in the Mediterranean area with a heterogeneous distribution of the genotypes between North and South Sicily; probands homozygotes for 35delG or presenting a T/T genotype are more apt to have a severe-to-profound HL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

References

  1. Szyfter W, Wróbel MJ, Szyfter-Harris J, Greczka G (2013) Hearing impairment in Polish infants. Epidemiology 24:333

    Article  PubMed  Google Scholar 

  2. Martines F, Porrello M, Ferrara M, Martines M, Martines E (2007) Newborn hearing screening project using transient evoked otoacoustic emissions: Western Sicily experience. Int J Pediatr Otorhinolaryngol 71:107–112

    Article  CAS  PubMed  Google Scholar 

  3. Martines F, Bentivegna D, Ciprì S, Costantino C, Marchese D et al (2012) On the threshold of effective well infant nursery hearing screening in Western Sicily. Int J Pediatr Otorhinolaryngol 76:423–427

    Article  PubMed  Google Scholar 

  4. Tekin M, Arons KS, Pandya A (2001) Advances in hereditary deafness. Lancet 358:1082–1090

    Article  CAS  PubMed  Google Scholar 

  5. Kenneson A, Van Naarden Braun K, Boyle C (2002) GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med 4:258–274

    Article  CAS  PubMed  Google Scholar 

  6. Nance WE (2003) The genetics of deafness. Ment Retard Dev Disabil Res Rev 9:109–119

    Article  PubMed  Google Scholar 

  7. Snoeckx Rikkert L, Patrick L et al (2005) GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet 77:945–957

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Bruzzone R, White TW, Paul DL (1996) Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem 238:1–27

    Article  CAS  PubMed  Google Scholar 

  9. Forge A, Becker D, Casalotti S et al (2003) Gap junctions in the inner ear: comparison of distribution patterns in different vertebrates and assessment of connexin composition in mammals. J Comp Neurol 467:207–231

    Article  PubMed  Google Scholar 

  10. Wangemann P (2002) K+ cycling and the endocochlear potential. Hear Res 165:1–9

    Article  CAS  PubMed  Google Scholar 

  11. Ballana E, Ventayol M, Rabionet R, Gasparini P, Estivill X (2009) Connexins and deafness homepage. http://davinci.crg.es/deafness/. Accessed October 26

  12. Denoyelle F, Weil D, Maw MA et al (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6(12):2173–2177

    Article  CAS  PubMed  Google Scholar 

  13. Morell RJ, Kim HJ, Hood LJ et al (1998) Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med 339(21):1500–1505

    Article  CAS  PubMed  Google Scholar 

  14. Abe S, Usami S, Shinkawa H, Kelley PM, Kimberling WJ (2000) Prevalent connexin 26gene (GJB2) mutations in Japanese. J Med Genet 37(1):41–43

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Niceta M, Fabiano C, Sammarco P et al (2007) Epidemiological study of nonsyndromic hearing loss in Sicilian newborns. Am J Med Genet A 143A(14):1666–1670

    Article  CAS  PubMed  Google Scholar 

  16. Martines F, Salvago P, Bentivegna D, Bartolone A, Dispenza F et al (2012) Audiologic profile of infants at risk: experience of a Western Sicily tertiary care centre. Int J Pediatr Otorhinolaryngol 76:1285–1291

    Article  PubMed  Google Scholar 

  17. Salvago P, Martines E, Martines F (2013) Prevalence and risk factors for sensorineural hearing loss: Western Sicily overview. Eur Arch Otorhinolaryngol 270(12):3049–3056. doi:10.1007/s00405-013-2379-2

    Article  PubMed  Google Scholar 

  18. Ballacchino A, Mucia M, Cocuzza S, Ferrara S, Martines E, Salvago P, Sireci F, Martines F (2013) Newborn hearing screening in Sicily: lesson learned. Acta Medica Mediterranea 29:731–734

    Google Scholar 

  19. Del Castillo FJ, Rodrı’guez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E et al (2005) A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet 42:588–594

    Article  PubMed Central  PubMed  Google Scholar 

  20. Bartolotta C, Salvago P, Cocuzza S, Fabiano C, Sammarco P, Martines F (2013) Identification of D179H, a novel missense GJB2 mutation in a Western Sicily family. Eur Arch Otorhinolaryngol. doi:10.1007/s00405-013-2613-y

    PubMed  Google Scholar 

  21. Cryns K, Orzan E, Murgia A, Huygen PL, Moreno F, del Castillo I, Chamberlin GP, Azaiez H, Prasad S, Cucci RA, Leonardi E, Snoeckx RL, Govaerts PJ, Van de Heyning PH, Van de Heyning CM, Smith RJ, Van Camp G (2004) A genotype–phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet 41(3):147–154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Berto A, Pellati D, Castiglione A, Busi M, Trevisi P, Gualandi F, Ferlini A, Martini A (2009) Audiological profiles and gjb2, gjb6 mutations: a retrospective study on genetic and clinical data from 2003 to 2008. Audiol Med 7:93–105

    Article  Google Scholar 

  23. Picciotti PM, Pietrobono R, Neri G, Paludetti G, Fetoni AR, Cianfrone F, Pomponi MG (2009) Correlation between GJB2 mutations and audiological deficits: personal experience. Eur Arch Otorhinolaryngol 266:489–494

    Article  PubMed  Google Scholar 

  24. Cama E, Melchionda S, Palladino T, Carella M, Santarelli R, Genovese E, Benettazzo F, Zelante L, Arslan E (2009) Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort. Int J Audiol 48(1):12–17

    Article  PubMed  Google Scholar 

  25. Gualandi F, Ravani A, Berto A, Sensi A, Trabanelli C, Falciano F, Trevisi P, Mazzoli M, Tibiletti MG, Cristofari E, Burdo S, Ferlini A, Martini A, Calzolari E (2002) Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet 112(1):38–45

    Article  CAS  PubMed  Google Scholar 

  26. Del Castillo I, Villamar M, Moreno-Pelayo MA, Del Castillo FJ, Alvarez A et al (2002) A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med 346:243–249

    Article  PubMed  Google Scholar 

  27. Roux AF, Pallares-Ruiz N, Vielle A, Faugère V, Templin C, Leprevost D, Artières F, Lina G, Molinari N, Blanchet P, Mondain M, Claustres M (2004) Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet 5:5

    Article  PubMed Central  PubMed  Google Scholar 

  28. Hişmi BO, Yilmaz ST, Incesulu A, Tekin M (2006) Effects of GJB2 genotypes on the audiological phenotype: variability is present for all genotypes. Int J Pediatr Otorhinolaryngol 70(10):1687–1694

    Article  PubMed  Google Scholar 

  29. Lucotte G (2007) High prevalences of carriers of the 35delG mutation of connexin 26 in the Mediterranean area. Int J Pediatr Otorhinolaryngol 71:741–746

    Article  PubMed  Google Scholar 

  30. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387:80–83

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Oshima A, Doi T, Mitsuoka K, Maeda S, Fujiyoshi Y (2003) Roles of Met-34, Cys-64, and Arg-75 in the assembly of human connexin 26: implication for key amino acid residues for channel formation and function. J Biol Chem 278:1807–1816

    Article  CAS  PubMed  Google Scholar 

  33. Wilcox SA, Saunders K, Osborn AH, Arnold A, Wunderlich J, Kelly T, Collins V, Wilcox LJ, McKinlay Gardner RJ, Kamarinos M, Cone-Wesson B, Williamson R, Dahl HH (2000) High frequency hearing loss correlated with mutations in the GJB2 gene. Hum Genet 106:399–405

    Article  CAS  PubMed  Google Scholar 

  34. Houseman MJ, Ellis LA, Pagnamenta A, Di WL, Rickard S, Osborn AH, Dahl HH, Taylor GR, Bitner-Glindzicz M, Reardon W, Mueller RF, Kelsell DP (2001) 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 38:20–25

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Wu BL, Lindeman N, Lip V, Adams A, Amato RS, Cox G, Irons M, Kenna M, Korf B, Raisen J, Platt O (2002) Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med 4:279–288

    Article  CAS  PubMed  Google Scholar 

  36. Griffith AJ, Chowdhry AA, Kurima K, Hood LJ, Keats B, Berlin CI, Morell RJ, Friedman TB (2000) Autosomal recessive nonsyndromic neurosensory deafness at DFNB1 not associated with the compound-heterozygous GJB2 (connexin 26) genotype M34T/167delT. Am J Hum Genet 67:745–749

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BioNeC), Sezione di Otorinolaringoiatria, Università degli Studi di Palermo, Via del Vespro, 129, 90127, Palermo, Italy

    Francesco Martines, Pietro Salvago, Sergio Ferrara & Federico Sireci

  2. Laboratorio di Genetica Molecolare, Ospedali Riuniti ‘Villa Sofia, V. Cervello’, Via Trabucco, 90100, Palermo, Italy

    Caterina Bartolotta, Carmelo Fabiano & Pietro Sammarco

  3. Department of Medical Surgical Specialities, ENT Clinic, University of Catania, Policlinico Universitario ‘‘Gaspare Rodolico’’, Via Santa Sofia, 68, 95125, Catania, Italy

    Salvatore Cocuzza

  4. Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi (Di.Bi.Me.F.), Sezione di Audiologia, Università degli Studi di Palermo, Via del Vespro, 129, 90127, Palermo, Italy

    Eleonora La Mattina, Marianna Mucia & Enrico Martines

  5. Via Autonomia Siciliana, 70, 90143, Palermo, Italy

    Francesco Martines

Authors
  1. Francesco Martines
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pietro Salvago
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caterina Bartolotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Salvatore Cocuzza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carmelo Fabiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sergio Ferrara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eleonora La Mattina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marianna Mucia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pietro Sammarco
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Federico Sireci
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Enrico Martines
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francesco Martines.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martines, F., Salvago, P., Bartolotta, C. et al. A genotype–phenotype correlation in Sicilian patients with GJB2 biallelic mutations. Eur Arch Otorhinolaryngol 272, 1857–1865 (2015). https://doi.org/10.1007/s00405-014-2970-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-014-2970-1

Keywords

Search

Navigation