Prevalence and evolutionary origins of the del(GJB6-D13S1830) mutation in the DFNB1 locus in hearing-impaired subjects: a multicenter study.
Mutations in GJB2, the gene encoding connexin-26 at the DFNB1 locus on 13q12, are found in as many as 50% of subjects with autosomal recessive, nonsyndromic prelingual hearing impairment. However, genetic diagnosis is complicated by the fact that 10%-50% of affected subjects with GJB2 mutations carry only one mutant allele. Recently, a deletion truncating the GJB6 gene (encoding connexin-30), near GJB2 on 13q12, was shown to be the accompanying mutation in approximately 50% of these deaf GJB2 heterozygotes in a cohort of Spanish patients, thus becoming second only to 35delG at GJB2 as the most frequent mutation causing prelingual hearing impairment in Spain. Here, we present data from a multicenter study in nine countries that shows that the deletion is present in most of the screened populations, with higher frequencies in France, Spain, and Israel, where the percentages of unexplained GJB2 heterozygotes fell to 16.0%-20.9% after screening for the del(GJB6-D13S1830) mutation. Our results also suggest that additional mutations remain to be identified, either in DFNB1 or in other unlinked genes involved in epistatic interactions with GJB2. Analysis of haplotypes associated with the deletion revealed a founder effect in Ashkenazi Jews and also suggested a common founder for countries in Western Europe. These results have important implications for the diagnosis and counseling of families with DFNB1 deafness.
Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain.
Ignacio
I
Del Castillo
Miguel A
MA
Moreno-Pelayo
Francisco J
FJ
Del Castillo
Zippora
Z
Brownstein
Sandrine
S
Marlin
Quint
Q
Adina
David J
DJ
Cockburn
Arti
A
Pandya
Kirby R
KR
Siemering
G Parker
GP
Chamberlin
Ester
E
Ballana
Wim
W
Wuyts
Andréa Trevas
AT
Maciel-Guerra
Araceli
A
Alvarez
Manuela
M
Villamar
Mordechai
M
Shohat
Dvorah
D
Abeliovich
Hans-Henrik M
HH
Dahl
Xavier
X
Estivill
Paolo
P
Gasparini
Tim
T
Hutchin
Walter E
WE
Nance
Edi L
EL
Sartorato
Richard J H
RJ
Smith
Guy
G
Van Camp
Karen B
KB
Avraham
Christine
C
Petit
Felipe
F
Moreno
D000072259:Connexin 26; D017630:Connexins / Q000235:genetics*; D017931:DNA Primers; D005060:Europe; D019143:Evolution, Molecular; D018703:Founder Effect; D005787:Gene Frequency; D005820:Genetic Testing; D006239:Haplotypes / Q000235:genetics; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics; D014481:United States
D017630:Connexins; D017931:DNA Primers; C000607042:GJB2 protein, human; D000072259:Connexin 26