A novel DFNB1 deletion allele supports the existence of a distant cis-regulatory region that controls GJB2 and GJB6 expression.
Eleven affected members of a large German-American family segregating recessively inherited, congenital, non-syndromic sensorineural hearing loss (SNHL) were found to be homozygous for the common 35delG mutation of GJB2, the gene encoding the gap junction protein Connexin 26. Surprisingly, four additional family members with bilateral profound SNHL carried only a single 35delG mutation. Previously, we demonstrated reduced expression of both GJB2 and GJB6 mRNA from the allele carried in trans with that bearing the 35delG mutation in these four persons. Using array comparative genome hybridization (array CGH), we have now identified on this allele a deletion of 131.4 kb whose proximal breakpoint lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6. This deletion, del(chr13:19,837,344-19,968,698), segregates as a completely penetrant DFNB1 allele in this family. It is not present in 528 persons with SNHL and monoallelic mutation of GJB2 or GJB6, and we have not identified any other candidate pathogenic copy number variation by arrayCGH in a subset of 10 such persons. Characterization of distant GJB2/GJB6 cis-regulatory regions evidenced by this allele may be required to find the 'missing' DFNB1 mutations that are believed to exist.
Genetics Program, Michigan State University, East Lansing, MI 48824, USA.
E
E
Wilch
H
H
Azaiez
R A
RA
Fisher
J
J
Elfenbein
A
A
Murgia
R
R
Birkenhäger
H
H
Bolz
S M
SM
Da Silva-Costa
I
I
Del Castillo
T
T
Haaf
L
L
Hoefsloot
H
H
Kremer
C
C
Kubisch
C
C
Le Marechal
A
A
Pandya
E L
EL
Sartorato
E
E
Schneider
G
G
Van Camp
W
W
Wuyts
R J H
RJ
Smith
K H
KH
Friderici
D000483:Alleles; D001483:Base Sequence; D002872:Chromosome Deletion; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation; D005820:Genetic Testing; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D019683:Penetrance; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26