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. 2017 Aug;62(8):789-795.
doi: 10.1038/jhg.2017.42. Epub 2017 Apr 13.

Update of the GJB2/DFNB1 mutation spectrum in Russia: a founder Ingush mutation del(GJB2-D13S175) is the most frequent among other large deletions

Elena A Bliznetz  1 , Maria R Lalayants  2 , Tatiana G Markova  2 , Oleg P Balanovsky  1   3 , Elena V Balanovska  1 , Roza A Skhalyakho  1   3 , Elvira A Pocheshkhova  4 , Natalya V Nikitina  5 , Sergey V Voronin  6 , Elena K Kudryashova  7 , Oleg S Glotov  8 , Alexander V Polyakov  1
Affiliations

Update of the GJB2/DFNB1 mutation spectrum in Russia: a founder Ingush mutation del(GJB2-D13S175) is the most frequent among other large deletions

Elena A Bliznetz et al. J Hum Genet. 2017 Aug.

Abstract

Although mutations in the GJB2 gene sequence make up the majority of variants causing autosomal-recessive non-syndromic hearing loss, few large deletions have been shown to contribute to DFNB1 deafness. Currently, genetic testing for DFNB1 hearing loss includes GJB2 sequencing and DFNB1 deletion analysis for two common large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854). Here, we report frequency in Russia, clinical significance and evolutionary origins of a 101 kb deletion, del(GJB2-D13S175), recently identified by us. In multiethnic cohort of 1104 unrelated hearing loss patients with biallelic mutations at the DFNB1 locus, the del(GJB2-D13S175) allele frequency of up to 0.5% (11/2208) was determined and this allele was shown to be predominantly associated with profound sensorineural hearing loss. Additionally, eight previously unpublished GJB2 mutations were described in this study. All patients carrying del(GJB2-D13S175) were of the Ingush ancestry. Among normal hearing individuals, del(GJB2-D13S175) was observed in Russian Republic of Ingushetia with a carrier rate of ~1% (2/241). Analysis of haplotypes associated with the deletion revealed a common founder in the Ingushes, with age of the deletion being ~3000 years old. Since del(GJB2-D13S175) was missed by standard methods of GJB2 analysis, del(GJB2-D13S175) detection has been added to our routine testing strategy for DFNB1 hearing loss.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic map of the six large deletions described at DFNB1 locus on chromosome 13q11-12. The DNA section encompasses eight genes (bold horizontal lines), the breakpoints of the deletions (dotted brackets). All elements are drawn approximately to scale. The del(GJB2-D13S175) mutation was investigated in this study. All genomic coordinates are based on Human Genome Build GRCh37.p13/hg19.
Figure 2
Figure 2
The cost-optimized DFNB1 testing strategy. The common mutation test lay in two reactions, a multiplex PCR with primer pairs for six deletions (c.35delG, c.313_326del14, c.235delC, c.167delT, c.358_360delGAG and GJB2-D13S175) and RLFP analysis of c.−23+1G>A, followed by gel-based fragment analysis to differentiate wild-type and mutation alleles.
See this image and copyright information in PMC

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