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

Abstract GJB2 was originally identified in severe, non-syndromic sensorineural hearing loss (SNHL), but was subsequently associated with mild and moderate SNHL. Given the increasing utilisation of genetic testing pre-conceptually, prenatally, and neonatally, it is crucial to understand genotype-phenotype correlations. This study evaluated the nature and frequency of GJB 2 variants in an Australian paediatric population with varying degrees of SNHL ascertained through newborn hearing screening. Audiograms from individuals with GJB2 variants and/or a GJB6 deletion ( GJB6 -D13S11830) were retrospectively reviewed ( n = 127). Two-thirds were biallelic (homozygous/compound heterozygous) for pathogenic/likely pathogenic variants of GJB2 and/or GJB6 ( n = 80). The most frequent variant was c.109 G > A, followed by c.35delG and c.101 T > C. Compared to biallelic carriage of other GJB2 variants, c.109 G > A positive individuals (homozygous/compound heterozygous) were more likely to have mild HL at their initial and latest audiograms ( p = 0.0004). Biallelic carriage of c.35delG was associated with moderately-severe or greater SNHL at both initial and latest audiograms ( p = 0.007). The c.101 T > C variant presented with milder SNHL and U-shaped audiograms ( p = 0.02). In this agnostically identified cohort, mild SNHL predominated in GJB2/GJB6 carriers in contrast to previous studies targeting individuals with significant loss. Consequently, c.109 G > A, associated with milder phenotypes, was the most frequent. This study provides valuable data to support prognostic confidence in genetic counselling.