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


METHODS
Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations.


METHODS
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.
Cryns
K
K
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Orzan
E
E
Murgia
A
A
Huygen
P L M
PL
Moreno
F
F
del Castillo
I
I
Chamberlin
G Parker
GP
Azaiez
H
H
Prasad
S
S
Cucci
R A
RA
Leonardi
E
E
Snoeckx
R L
RL
Govaerts
P J
PJ
Van de Heyning
P H
PH
Van de Heyning
C M
CM
Smith
R J H
RJ
Van Camp
G
G
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000375:Aging; D000483:Alleles; D001299:Audiometry; D001530:Belgium; D002648:Child; D002675:Child, Preschool; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005820:Genetic Testing; D005838:Genotype; D034381:Hearing Loss / Q000145:classification / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D007558:Italy; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D012189:Retrospective Studies; D013030:Spain; D014481:United States
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26