title: GJB2 mutations and degree of hearing loss: a multicenter study.
abstract: Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Rikkert L
authors.initials: RL
authors.lastname: Snoeckx
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: Delphine
authors.initials: D
authors.lastname: Feldmann
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.forename: Françoise
authors.initials: F
authors.lastname: Denoyelle
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Waligora
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Mueller-Malesinska
authors.forename: Agneszka
authors.initials: A
authors.lastname: Pollak
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.forename: Alessandra
authors.initials: A
authors.lastname: Murgia
authors.forename: Eva
authors.initials: E
authors.lastname: Orzan
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.forename: Umberto
authors.initials: U
authors.lastname: Ambrosetti
authors.forename: Ewa
authors.initials: E
authors.lastname: Nowakowska-Szyrwinska
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bal
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.forename: Doris
authors.initials: D
authors.lastname: Nekahm-Heis
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Olga
authors.initials: O
authors.lastname: Bendova
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Kenna
authors.forename: Anna
authors.initials: A
authors.lastname: Frangulov
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Armagan
authors.initials: A
authors.lastname: Incesulu
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.forename: Desirée
authors.initials: D
authors.lastname: du Sart
authors.forename: Lucy
authors.initials: L
authors.lastname: Jenkins
authors.forename: Deirdre
authors.initials: D
authors.lastname: Lucas
authors.forename: Maria
authors.initials: M
authors.lastname: Bitner-Glindzicz
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
authors.forename: Zippora
authors.initials: Z
authors.lastname: Brownstein
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
authors.forename: Felipe
authors.initials: F
authors.lastname: Moreno
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Blin
authors.forename: Markus
authors.initials: M
authors.lastname: Pfister
authors.forename: Istvan
authors.initials: I
authors.lastname: Sziklai
authors.forename: Timea
authors.initials: T
authors.lastname: Toth
authors.forename: Philip M
authors.initials: PM
authors.lastname: Kelley
authors.forename: Edward S
authors.initials: ES
authors.lastname: Cohn
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Pascale
authors.initials: P
authors.lastname: Hilbert
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Roux
authors.forename: Michel
authors.initials: M
authors.lastname: Mondain
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Tuija
authors.initials: T
authors.lastname: Löppönen
authors.forename: Heikki
authors.initials: H
authors.lastname: Löppönen
authors.forename: Agnete
authors.initials: A
authors.lastname: Parving
authors.forename: Karen
authors.initials: K
authors.lastname: Gronskov
authors.forename: Iris
authors.initials: I
authors.lastname: Schrijver
authors.forename: Joseph
authors.initials: J
authors.lastname: Roberson
authors.forename: Francesca
authors.initials: F
authors.lastname: Gualandi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Martini
authors.forename: Geneviéve
authors.initials: G
authors.lastname: Lina-Granade
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pallares-Ruiz
authors.forename: Céu
authors.initials: C
authors.lastname: Correia
authors.forename: Graça
authors.initials: G
authors.lastname: Fialho
authors.forename: Kim
authors.initials: K
authors.lastname: Cryns
authors.forename: Nele
authors.initials: N
authors.lastname: Hilgert
authors.forename: Paul
authors.initials: P
authors.lastname: Van de Heyning
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Nishimura
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001299:Audiometry; D002648:Child; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D034381:Hearing Loss / Q000235:genetics* / Q000503:physiopathology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009154:Mutation; D012189:Retrospective Studies; D012720:Severity of Illness Index
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26