This review integrates molecular, clinical, and translational data to provide an updated understanding of GJB2-related deafness and its emerging treatment landscape. Truncating mutations in GJB2 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 GJB6 and CRYL1, can influence HL severity when compounded with other pathogenic GJB2 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 GJB2-positive children yields superior speech and language development compared with non-GJB2 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 GJB2-related HL and highlights how gene-based strategies are poised to change the treatment of this condition.

Background/Objectives: Although genetic testing is recommended for pediatric hearing loss, referral rates within otology and audiology practices remain low. This study evaluated referral rates, referral pathways, and genetics appointment completion before and after implementation of a quality improvement (QI) referral protocol in an ethnically diverse pediatric cohort. Methods: Phase 1 (January–August 2023) included chart reviews of 88 pediatric patients with hearing loss to assess whether genetics referrals were made and completed. Data collected included demographics, referral modality (clinical note documentation, routed note to genetics, or direct referral order), and appointment status. In Phase 2 (September 2023–September 2024), a standardized referral protocol was implemented requiring all newly diagnosed patients to be referred using one of three predefined pathways. Providers received brief training and reminder cards. Chart reviews were then conducted for an additional 114 patients. Results: A total of 202 patients were included (Phase 1: n = 88; Phase 2: n = 114). Following protocol implementation, the proportion of patients with any documented genetics referral increased significantly (35.2% vs. 68.4%, χ² = 22.03, p < 0.001). Referral order placement, documentation, and note routing increased across all referral modalities (all p < 0.001). Genetics appointment completion also improved significantly, from 11.4% in Phase 1 to 38.6% in Phase 2 (p < 0.001). Conclusions: Genetic referrals for pediatric hearing loss remain underutilized but improved substantially following implementation of a standardized referral protocol. These findings highlight the importance of optimizing referral pathways and providing ongoing provider education. QI initiatives represent a practical strategy to enhance access to genetic evaluation and support precision care.