HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS REGISTER		Author Keyword(s) Vol Page [Advanced]

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this link to a friend Similar articles in this journal Similar articles in PubMed Add article to my folders Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cryns, K Articles by Van Camp, G Search for Related Content PubMed PubMed Citation Articles by Cryns, K Articles by Van Camp, G

A genotype-phenotype correlation for GJB2 (connexin 26) deafness

¹ Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
² Otosurgery Unit, University Hospital Padua, Padua, Italy
³ Department of Paediatrics, University of Padua, Padua, Italy
⁴ Department of Otorhinolaryngology, University Medical Centre St Radboud, Nijmegen, Netherlands
⁵ Unidad de Genetica Molecular, Hospital Ramon y Cajal, Madrid, Spain
⁶ Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, USA
⁷ The Ear Group, Antwerp-Deurne, Belgium
⁸ Department of Otolaryngology, University of Antwerp, Antwerp, Belgium

Correspondence to:
Guy Van Camp
Department of Medical Genetics, University of Antwerp-UIA, Universiteitsplein 1, B-2610 Antwerp, Belgium; guy.vancamp{at}ua.ac.be] Introduction: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test.

Objective: To assess a possible genotype-phenotype correlation for GJB2.

Design: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations.

Subjects: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations.

Results: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes.

Conclusions: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

Abbreviations: ASPCR, allele-specific polymerase chain reaction; HL, hearing loss; ISO, International Standards Organization; PTA, pure tone average; SSCP, single strand conformational polymorphism

This article has been cited by other articles:

				H-H M Dahl, S E Tobin, Z Poulakis, F W Rickards, X Xu, L Gillam, J Williams, K Saunders, B Cone-Wesson, and M Wake The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children J. Med. Genet., November 1, 2006; 43(11): 850 - 855. [Abstract] [Full Text] [PDF]

				M. Bicego, M. Beltramello, S. Melchionda, M. Carella, V. Piazza, L. Zelante, F. F. Bukauskas, E. Arslan, E. Cama, S. Pantano, et al. Pathogenetic role of the deafness-related M34T mutation of Cx26 Hum. Mol. Genet., September 1, 2006; 15(17): 2569 - 2587. [Abstract] [Full Text] [PDF]

				C. C. Morton and W. E. Nance Newborn Hearing Screening -- A Silent Revolution N. Engl. J. Med., May 18, 2006; 354(20): 2151 - 2164. [Full Text] [PDF]

				D. L. Beahm, A. Oshima, G. M. Gaietta, G. M. Hand, A. E. Smock, S. N. Zucker, M. M. Toloue, A. Chandrasekhar, B. J. Nicholson, and G. E. Sosinsky Mutation of a Conserved Threonine in the Third Transmembrane Helix of {alpha}- and beta-Connexins Creates a Dominant-negative Closed Gap Junction Channel J. Biol. Chem., March 24, 2006; 281(12): 7994 - 8009. [Abstract] [Full Text] [PDF]

				C. G. S. Palmer, A. Martinez, Y. Sininger, N. Shapiro, W. W. Grody, and L. A. Schimmenti Prelingual Siblings of Children With GJB2 Hearing Loss: Issues to Consider Arch Otolaryngol Head Neck Surg, November 1, 2005; 131(11): 1020 - 1022. [Full Text] [PDF]

				S. Marlin, D. Feldmann, H. Blons, N. Loundon, I. Rouillon, S. Albert, P. Chauvin, E.-N. Garabedian, R. Couderc, S. Odent, et al. GJB2 and GJB6 Mutations: Genotypic and Phenotypic Correlations in a Large Cohort of Hearing-Impaired Patients Arch Otolaryngol Head Neck Surg, June 1, 2005; 131(6): 481 - 487. [Abstract] [Full Text] [PDF]