Diagnostic pitfalls for GJB2‐related hearing loss: A novel deletion detected by Array‐CGH analysis in a Japanese patient with congenital profound hearing loss

GJB2 gene mutations are known to be the most common cause of hereditary hearing loss worldwide. Therefore, genetic testing for GJB2 mutations is one of the most important screening processes for the molecular diagnosis of deafness. However, some caution is due in the diagnosis of hearing loss based on GJB2 screening as several types of large deletions have been reported. Here, we report a novel deletion (copy number variation: CNV) in the GJB2 gene observed in a Japanese patient presenting with profound hearing loss. This deletion was observed in trans to a GJB2‐mutated allele carrying the GJB2:{"type":"entrez-nucleotide","attrs":{"text":"NM_004004.5","term_id":"195539329","term_text":"NM_004004.5"}}NM_004004.5:c.427C>T:p.R143W mutation by PCR fragment analysis. It should be noted that this deletion was identified as homozygosity of c.427C>T:p.R143W by Sanger sequencing. Array‐CGH analysis showed the deleted segment started in the middle of the GJB2 coding region and extended for at least eight thousand base pairs, although the GJB6 gene remained intact. The distal breakpoint downstream of the GJB6 gene differed from the breakpoints of the known DFNB1 locus deletions. This partial deletion in the GJB2 gene highlights the need for further improvements in GJB2 screening. Inherited sensorineural hearing loss (HL) is an extremely heterogeneous group of sensory disorders in humans. The overall incidence is estimated to be one in approximately 1000 newborns.1, 2 The GJB2 gene (MIM# 121011), which encodes the gap junction protein connexin 26 (Cx26), is the most common genetic etiology associated with congenital HL worldwide, with the mutation spectrums known to vary among different ethnic groups.3, 4, 5 The GJB2 gene is a small gene composed of two exons, one of which possesses a 678‐bp coding sequence. As screening of the GJB2 gene is considered a standard, first‐step approach in the diagnosis of genetic hereditary HL, it is not surprising that more than 300 mutations in the GJB2 gene sequence have been described (The Human Gene Mutation Database). In general terms, GJB2‐related congenital HL develops through a biallelic mutation. Among patients with a single GJB2 heterozygous status, some caution is due in the diagnosis of hearing loss based on GJB2 screening as a large deletion located in the 13q12 region encompassing the GJB2 and GJB6 genes (the so‐called DFNB1 locus) is sometimes seen in trans with GJB2‐coding region variants. Therefore, the potential for such deletions to be present should be kept in mind. To date, six large deletions contributing to HL have been identified in the DFNB1 region.6, 7, 8, 9, 10, 11 Here, we report for the first time a novel large deletion in the GJB2 gene in one Japanese family with nonsyndromic HL. The present work highlighted the diagnostic pitfalls of GJB2‐related hearing loss and could expand the pathogenic spectrum and strengthen our understanding of the complicated mechanisms by which GJB2 gives rise to HL.