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 GJB2 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.