title: GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.
abstract: OBJECTIVE
  To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with DFNB1.
  
  
  METHODS
  Case series.
  
  
  METHODS
  Collaborative study in referral centers, institutional practice. Patients A total of 256 hearing-impaired patients selected on the basis of the presence of biallelic mutations in GJB2 or the association of 1 GJB2 mutation with the GJB6 deletion (GJB6-D13S1830)del.
  
  
  METHODS
  The prevalence of GJB2 mutations and the GJB6 deletion and audiometric phenotypes related to the most frequent genotypes.
  
  
  RESULTS
  Twenty-nine different GJB2 mutations were identified. Allelic frequency of 35delG was 69%, and the other common mutations, 313del14, E47X, Q57X, and L90P, accounted for 2.6% to 2.9% of the variants. Concerning GJB6, (GJB6-D13S1830)del accounted for 5% of all mutated alleles and was observed in 25 of 93 compound heterozygous patients. Three novel GJB2 mutations, 355del9, V95M, and 573delCA, were identified. Hearing impairment was frequently less severe in compound heterozygotes 35delG/L90P and 35delG/N206S than in 35delG homozygotes. Moderate or mild hearing impairment was more frequent in patients with 1 or 2 noninactivating mutations than in patients with 2 inactivating mutations. Of 93 patients, hearing loss was stable in 73, progressive in 21, and fluctuant in 2. Progressive hearing loss was more frequent in patients with 1 or 2 noninactivating mutations than in those with 2 inactivating mutations. In 49 families, hearing loss was compared between siblings with similar genotypes, and variability in terms of severity was found in 18 families (37%).
  
  
  CONCLUSIONS
  Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness.
authors.affiliation: Unité de Génétique Médicale, INSERM U587, Hôpital d'Enfants Armand-Trousseau, AP-HP, Université Paris VI, Paris, France. sandrine.marlin@trs.ap-hop-paris.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Delphine
authors.initials: D
authors.lastname: Feldmann
authors.forename: Hélène
authors.initials: H
authors.lastname: Blons
authors.forename: Natalie
authors.initials: N
authors.lastname: Loundon
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouillon
authors.forename: Sébastien
authors.initials: S
authors.lastname: Albert
authors.forename: Pierre
authors.initials: P
authors.lastname: Chauvin
authors.forename: Eréa-Noël
authors.initials: EN
authors.lastname: Garabédian
authors.forename: Rémy
authors.initials: R
authors.lastname: Couderc
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Alain
authors.initials: A
authors.lastname: Joannard
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmerber
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.forename: Jacques
authors.initials: J
authors.lastname: Leman
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.forename: Hélène
authors.initials: H
authors.lastname: Catros
authors.forename: Cédric
authors.initials: C
authors.lastname: Lemarechal
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Marie-Madeleine
authors.initials: MM
authors.lastname: Eliot
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Delaunoy
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Catherine
authors.initials: C
authors.lastname: Calais
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouin-Garraud
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Obstoy
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Françoise
authors.initials: F
authors.lastname: Duriez
authors.forename: Florence
authors.initials: F
authors.lastname: Fellmann
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Hélias
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Vigneron
authors.forename: Bettina
authors.initials: B
authors.lastname: Montaut
authors.forename: Dominique
authors.initials: D
authors.lastname: Matin-Coignard
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.forename: Patricia
authors.initials: P
authors.lastname: Lewin
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.forename: Françoise
authors.initials: F
authors.lastname: Denoyelle
mesh_terms: D002872:Chromosome Deletion; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005838:Genotype; D006311:Hearing Disorders / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011446:Prospective Studies
chemical_list: D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26