GJB2 mutations and degree of hearing loss: a multicenter study.
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.
Snoeckx
Rikkert L
RL
Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Huygen
Patrick L M
PL
Feldmann
Delphine
D
Marlin
Sandrine
S
Denoyelle
Françoise
F
Waligora
Jaroslaw
J
Mueller-Malesinska
Malgorzata
M
Pollak
Agneszka
A
Ploski
Rafal
R
Murgia
Alessandra
A
Orzan
Eva
E
Castorina
Pierangela
P
Ambrosetti
Umberto
U
Nowakowska-Szyrwinska
Ewa
E
Bal
Jerzy
J
Wiszniewski
Wojciech
W
Janecke
Andreas R
AR
Nekahm-Heis
Doris
D
Seeman
Pavel
P
Bendova
Olga
O
Kenna
Margaret A
MA
Frangulov
Anna
A
Rehm
Heidi L
HL
Tekin
Mustafa
M
Incesulu
Armagan
A
Dahl
Hans-Henrik M
HH
du Sart
Desirée
D
Jenkins
Lucy
L
Lucas
Deirdre
D
Bitner-Glindzicz
Maria
M
Avraham
Karen B
KB
Brownstein
Zippora
Z
del Castillo
Ignacio
I
Moreno
Felipe
F
Blin
Nikolaus
N
Pfister
Markus
M
Sziklai
Istvan
I
Toth
Timea
T
Kelley
Philip M
PM
Cohn
Edward S
ES
Van Maldergem
Lionel
L
Hilbert
Pascale
P
Roux
Anne-Françoise
AF
Mondain
Michel
M
Hoefsloot
Lies H
LH
Cremers
Cor W R J
CW
Löppönen
Tuija
T
Löppönen
Heikki
H
Parving
Agnete
A
Gronskov
Karen
K
Schrijver
Iris
I
Roberson
Joseph
J
Gualandi
Francesca
F
Martini
Alessandro
A
Lina-Granade
Geneviéve
G
Pallares-Ruiz
Nathalie
N
Correia
Céu
C
Fialho
Graça
G
Cryns
Kim
K
Hilgert
Nele
N
Van de Heyning
Paul
P
Nishimura
Carla J
CJ
Smith
Richard J H
RJ
Van Camp
Guy
G
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
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26