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.
Del Castillo
Ignacio
I
Unidad de Genética Molecular, Hospital Ramón y Cajal, Madrid, Spain.
Moreno-Pelayo
Miguel A
MA
Del Castillo
Francisco J
FJ
Brownstein
Zippora
Z
Marlin
Sandrine
S
Adina
Quint
Q
Cockburn
David J
DJ
Pandya
Arti
A
Siemering
Kirby R
KR
Chamberlin
G Parker
GP
Ballana
Ester
E
Wuyts
Wim
W
Maciel-Guerra
Andréa Trevas
AT
Alvarez
Araceli
A
Villamar
Manuela
M
Shohat
Mordechai
M
Abeliovich
Dvorah
D
Dahl
Hans-Henrik M
HH
Estivill
Xavier
X
Gasparini
Paolo
P
Hutchin
Tim
T
Nance
Walter E
WE
Sartorato
Edi L
EL
Smith
Richard J H
RJ
Van Camp
Guy
G
Avraham
Karen B
KB
Petit
Christine
C
Moreno
Felipe
F
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