GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.
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.
Marlin
Sandrine
S
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
Feldmann
Delphine
D
Blons
Hélène
H
Loundon
Natalie
N
Rouillon
Isabelle
I
Albert
Sébastien
S
Chauvin
Pierre
P
Garabédian
Eréa-Noël
EN
Couderc
Rémy
R
Odent
Sylvie
S
Joannard
Alain
A
Schmerber
Sébastien
S
Delobel
Bruno
B
Leman
Jacques
J
Journel
Hubert
H
Catros
Hélène
H
Lemarechal
Cédric
C
Dollfus
Hélène
H
Eliot
Marie-Madeleine
MM
Delaunoy
Jean-Louis
JL
David
Albert
A
Calais
Catherine
C
Drouin-Garraud
Valérie
V
Obstoy
Marie-Françoise
MF
Goizet
Cyril
C
Duriez
Françoise
F
Fellmann
Florence
F
Hélias
Jocelyne
J
Vigneron
Jacqueline
J
Montaut
Bettina
B
Matin-Coignard
Dominique
D
Faivre
Laurence
L
Baumann
Clarisse
C
Lewin
Patricia
P
Petit
Christine
C
Denoyelle
Françoise
F
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
D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26