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

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.

[1]  K. Lange,et al.  Evaluation of Cx26/GJB2 in German hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and ‐493del10 , 2003, Human mutation.

[2]  R. Williamson,et al.  High frequency hearing loss correlated with mutations in the GJB2 gene , 2000, Human Genetics.

[3]  H. Pratt,et al.  Otoacoustic emissions and brainstem evoked potentials in compound carriers of connexin 26 mutations , 2003, Hearing Research.

[4]  G. Camp,et al.  The hereditary hearing loss homepage , 1997 .

[5]  G. Taylor,et al.  A common founder for the 35delG GJB2gene mutation in connexin 26 hearing impairment , 2001, Journal of medical genetics.

[6]  S. Marlin,et al.  Loss‐of‐function and residual channel activity of connexin26 mutations associated with non‐syndromic deafness , 2003, FEBS letters.

[7]  H. Rehm,et al.  Connexin 26 studies in patients with sensorineural hearing loss. , 2001, Archives of otolaryngology--head & neck surgery.

[8]  C. Petit,et al.  Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling , 1999, The Lancet.

[9]  Vickie Thomson,et al.  The Colorado newborn hearing screening project, 1992-1999: on the threshold of effective population-based universal newborn hearing screening. , 2002, Pediatrics.

[10]  F. E. Offeciers,et al.  A Two-stage Bipodal Screening Model for Universal Neonatal Hearing Screening , 2001, Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology.

[11]  D. Kelsell,et al.  Connexin mutations in deafness , 1998, Nature.

[12]  K. Elbedour,et al.  Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss , 1998, Human mutation.

[13]  G. Utermann,et al.  Sensorineural hearing loss and the incidence of Cx26 mutations in Austria , 2001, European Journal of Human Genetics.

[14]  J. W. Askew,et al.  Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. , 1998, American journal of human genetics.

[15]  W. Kimberling,et al.  Prevalent connexin 26 gene (GJB2) mutations in Japanese , 2000, Journal of medical genetics.

[16]  K. Avraham,et al.  The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population , 1999, Human Genetics.

[17]  A. Murgia,et al.  Molecular genetics applied to clinical practice: the Cx26 hearing impairment. , 1999, British journal of audiology.

[18]  F. Zacchello,et al.  Cx26 deafness: mutation analysis and clinical variability , 1999, Journal of medical genetics.

[19]  Wen‐Teng Chang,et al.  Functional analysis of connexin‐26 mutants associated with hereditary recessive deafness , 2003, Journal of neurochemistry.

[20]  G. B. Schaefer,et al.  Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1) , 1999, Pediatrics.

[21]  M. J. Lee,et al.  Heteromeric gap junction channels in rat hepatocytes in which the expression of connexin26 is induced. , 1998, Molecules and cells.

[22]  X. Estivill,et al.  Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene , 1999, Human Genetics.

[23]  E. Winterhager,et al.  Mutations in the connexin26/GJB2 gene are the most common event in non‐syndromic hearing loss among the German population , 2001, Human mutation.

[24]  K. Stauffer.  The Gap Junction Proteins β1-Connexin (Connexin-32) and β2-Connexin (Connexin-26) Can Form Heteromeric Hemichannels , 1995 .

[25]  D. Yannoukakos,et al.  Prevalence of GJB2 mutations in prelingual deafness in the Greek population. , 2002, International journal of pediatric otorhinolaryngology.

[26]  A. Kenneson,et al.  GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: A HuGE review , 2002, Genetics in Medicine.

[27]  Tom Walsh,et al.  Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East , 2002, Human Genetics.

[28]  G. Taylor,et al.  Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene mutations--molecular and audiological findings. , 1999, International journal of pediatric otorhinolaryngology.

[29]  Thomas W. White,et al.  Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma , 1998, Human Genetics.

[30]  A Forge,et al.  Properties of connexin26 gap junctional proteins derived from mutations associated with non-syndromal heriditary deafness. , 1999, Human molecular genetics.

[31]  X. Estivill,et al.  Connexin-26 mutations in sporadic and inherited sensorineural deafness , 1998, The Lancet.

[32]  R. Bruzzone,et al.  Connexin 26 gene linked to a dominant deafness , 1998, Nature.

[33]  A. Viel,et al.  Four novel MSH2 and MLH1 frameshift mutations and occurrence of a breast cancer phenocopy in hereditary nonpolyposis colorectal cancer , 2001, Human mutation.

[34]  C. Petit,et al.  Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. , 1997, Human molecular genetics.

[35]  V. Thomson,et al.  Newborn Hearing Screening: The Great Omission , 1998, Pediatrics.

[36]  P. Latour,et al.  A novel C202F mutation in the connexin26 gene (GJB2) associated with autosomal dominant isolated hearing loss , 2000, Journal of medical genetics.

[37]  Xavier Estivill,et al.  Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. , 2002, Human Genetics.

[38]  V. Sheffield,et al.  Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. , 1999, JAMA.

[39]  F. Telischi,et al.  The prevalence of connexin 26 (GJB2) mutations in the Chinese population , 2002, Human Genetics.

[40]  N. E. MORTON,et al.  Genetic Epidemiology of Hearing Impairment , 1991, Annals of the New York Academy of Sciences.

[41]  K. Stauffer.  The gap junction proteins beta 1-connexin (connexin-32) and beta 2-connexin (connexin-26) can form heteromeric hemichannels. , 1995, The Journal of biological chemistry.

[42]  Paolo Gasparini,et al.  Hearing loss: frequency and functional studies of the most common connexin26 alleles. , 2002, Biochemical and biophysical research communications.

[43]  E. Rappaport,et al.  Homozygosity for the V37I Connexin 26 mutation in three unrelated children with sensorineural hearing loss , 2002, Clinical genetics.

[44]  G. Utermann,et al.  Progressive hearing loss, and recurrent sudden sensorineural hearing loss associated with GJB2 mutations – phenotypic spectrum and frequencies of GJB2 mutations in Austria , 2002, Human Genetics.

[45]  X. Estivill,et al.  High carrier frequency of the 35delG deafness mutation in European populations , 2000, European Journal of Human Genetics.

[46]  Lee Mj,et al.  Heteromeric gap junction channels in rat hepatocytes in which the expression of connexin26 is induced. , 1998 .

[47]  C. Petit,et al.  Connexin 26 gene mutations in congenitally deaf children: pitfalls for genetic counseling. , 2001, Archives of otolaryngology--head & neck surgery.

[48]  G. Green,et al.  Genetic testing for hereditary hearing loss: Connexin 26 (GJB2) allele variants and two novel deafness‐causing mutations (R32C and 645‐648delTAGA) , 2000, Human mutation.

[49]  A. Griffith,et al.  Auditory function and the M34T allele of connexin 26. , 2002, Archives of Otolaryngology - Head and Neck Surgery.

[50]  X. Estivill,et al.  Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. , 1997, Human molecular genetics.