Diagnostics Service of
the Molecular Otolaryngology & Renal Research Laboratories is a Joint
Commission-approved CLIA-accredited diagnostic laboratory that
offers mutation screening of several genes.
DFNB1 (OMIM#: 220290)
Two different genes cause hearing loss at this
locus, which maps to chromosome 13q11-q12:GJB2,
encoding Connexin 26; and GJB6,
encoding Connexin 30.
Connexin 26, CX26)
CX26 (OMIM#: *121011) is
a gap junction protein expressed in the supporting cells of the
cochlea. The gene, GJB2,
contains 2 exons, the second of which encodes the 226 amino acid
protein CX26. Mutations in GJB2 are
found in ~50% of persons with autosomal recessive nonsyndromic
hearing loss. Over 100 different mutations have been identified.
Connexin 30, CX30)
*604418) is also
a gap junction protein. Lerer and colleagues identified a
deletion upstream of GJB2, which included the first exon of GJB6
in 2001. Del Castillo and colleagues characterized this deletion
as a 342kb fragment of chromosome 13 that included D13S1830 in
addition to a portion of GJB6, and so this deletion is commonly
known as the del(GJB6-D13S1830) mutation. It cosegregates with
mutations in GJB2 to cause recessively inherited deafness at the
DFNB1 locus. A recent multicenter study investigating the
mutation spectrum in over 1500 deaf persons from 16 countries
found this mutation to represent 1.67% of mutations at the DFNB1
locus (Van Camp, et al. 2005). A second smaller deletion,
del(GJB6-D13S1854), also causes deafness at the DFNB1 locus.
MORL screening methodology
Over 97% of the identified mutations at the DFNB1
locus occur in exon 2 of GJB2 (Van
Camp, et al 2005). We have adopted a tiered screening process
focusing first on exon 2 of GJB2 and
the two GJB6-containing deletions. The finding of two
deafness-causing mutations is consistent with the diagnosis of
hearing loss at the DFNB1 locus. If one only mutation is found,
mutation screening for the splice site mutation in exon 1 of GJB2 (IVS1
+ 1 G>A) is completed. If no deafness-causing mutations are
found, the diagnosis of hearing loss at the DFNB1 locus is
excluded based on today’s standards. (GJB2 mutation
screening is performed by amplification of oligonucleotide
primers that flank each exon followed by bi-directional
sequencing. Screening for the del(GJB6-D13S1830) and
del(GJB6-D13S1854) mutations is completed by PCR
amplification of oligonucleotide primers flanking and within the
deletion breakpoints. Products are run on agarose gel and sized
to determine presence or absence of a deletion.)
Figure legend: Lane 1, 1Kb + ladder; lane 2, wild type control;
lane 3, del(GJB6-D13S1854) homozygote; lane 4,
del(GJB6-D13S1830) heterozygote; lanes 5-7, normal controls.
Sensitivity is greater than 98%.
Turn around time is approximately 8 weeks
(Average TAT - 29 days).
Indications for screening
This test is appropriate for any patient with
congenital hearing impairment with negative family history.
GeneTests GeneReviews – Nonsyndromic
Hearing Loss and Deafness, DFNB1
Kelsell, D. P. et al.: Connexin
26 mutations in hereditary non-syndromic sensorineural deafness. Nature
387: 80-83, 1997.
PubMed ID: 9139825
Del Castillo, I. et al.: A
deletion involving the connexin 30 gene in nonsyndromic hearing
Eng. J. Med. 346: 243-249, 2002.
PubMed ID: 11807148
Del Castillo, I. et al.: Prevalence
and evolutionary origins of the del(GJB6-D13S1830) mutation in
the DFNB1 locus in hearing-impaired subjects: a multicenter
study. Am J Hum Genet. 2003 Dec;73(6):1452-8. Epub 2003
PubMed ID: 14571368
Azaiez,H.et al.: GJB2:
The spectrum of deafness-causing allele variants and their
PubMed ID: 15365987
Del Castillo, F. J. et al.: A
Novel Deletion Involving the Connexin-30 Gene, del(GJB6-D13S1854),
Found in trans with
Mutations in the GJB2 Gene
(Connexin-26) in Subjects with Autosomal Recessive Non-Syndromic
Hearing Impairment. J Med Genet 2005; 42: 588-594.
PubMed ID: 15994881
Snoeckx, R. L. et al.: GJB2
Mutations and Degree of Hearing Loss: A Multicenter Study
Am J Hum Genet. 77:945-957, 2005.
PubMed ID: 16380907