GJB2-Related Hearing Loss: Genotype-Phenotype Correlations, Natural History, and Emerging Therapeutic Strategies

This review integrates molecular, clinical, and translational data to provide an updated understanding of <i>GJB2</i>-related deafness and its emerging treatment landscape. Truncating mutations in <i>GJB2</i> typically cause severe-profound hearing loss (HL) phenotypes, whereas non-truncating alleles are often associated with milder or progressive phenotypes. Geographic variation in variant prevalence contributes to regional differences in disease burden. Beyond the coding region, deletions and cis-regulatory mutations within the DFNB1 locus, including <i>GJB6</i> and <i>CRYL1</i>, can influence HL severity when compounded with other pathogenic <i>GJB2</i> variants. DFNB1 hearing loss generally presents as symmetric, bilateral, and flat to gently sloping across frequencies, with preserved cochlear neurons that support excellent cochlear implant (CI) outcomes. Early implantation CI in <i>GJB2</i>-positive children yields superior speech and language development compared with non-<i>GJB2</i> etiologies. Emerging therapies include dual-AAV (AAV1 + AAV-ie/ScPro) delivery, achieving cell-specific Cx26 restoration, adenine base-editing for dominant-negative variants, and allele-specific suppression using RNA interference or antisense oligonucleotides. Concurrent progress in human iPSC-derived cochlear organoids provides a physiologic model to advance toward clinical trials. By integrating genotype-phenotype correlations, natural history insights, and advances in molecular therapeutics, this review presents a comprehensive update on <i>GJB2</i>-related HL and highlights how gene-based strategies are poised to change the treatment of this condition.