The congenital hearing phenotype in GJB2 in Queensland, Australia: V37I and mild hearing loss predominates

Abstract

Guidelines recommend GJB2 (connexin 26) and GJB6 (connexin 30) testing for bilateral non-syndromic sensorineural hearing loss (SNHL). However, associated audiological phenotypes vary. There is limited Australian data on GJB2 variant frequency and associated phenotypes. Audiograms from a paediatric cohort with SNHL, predominantly identified through newborn hearing screening and carrying GJB2 variants and/or a GJB6 deletion (GJB6-D13S11830) were retrospectively reviewed (n = 127). Two thirds were homozygous or compound heterozygous for pathogenic or likely pathogenic variants of GJB2 and/or GJB6 (n = 80). The most frequent variant, c.109G > A, occurred in homozygous (n = 32), compound heterozygous (n = 8) and heterozygous (n = 5) states. Compared to homozygous/compound heterozygous carriage of other GJB2 variants, c.109G > A positive individuals (homozygous/compound heterozygous) were more likely to have mild HL at their initial (p = 0.00004) and latest audiograms (p = 0.0004). Homozygous/compound heterozygous carriage of c.35delG was associated with moderately-severe or greater HL at both initial (p = 0.007) and latest (p = 0.007) audiograms. The c.101T > C variant presented with milder HL and U-shaped audiograms (p = 0.02). In this agnostically identified cohort, mild HL predominated in GJB2/GJB6 carriers in contrast to previous studies targeting individuals with significant loss. Consequently, c.109G > A, associated with milder phenotypes, was the most frequent. This data provides valuable, balanced prognostic information for preconception, prenatal and paediatric counselling of couples and families carrying these variants.