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

## TL;DR

This paper reviews how GJB2 gene mutations cause hearing loss, how symptoms vary by mutation type, and new treatments being developed.

## Contribution

The paper provides updated genotype-phenotype correlations and highlights emerging gene-based therapies for GJB2-related hearing loss.

## Key findings

- Truncating GJB2 mutations typically cause severe-profound hearing loss, while non-truncating mutations are linked to milder or progressive forms.
- Early cochlear implantation in GJB2-positive children improves speech and language outcomes.
- Emerging therapies include dual-AAV delivery, base-editing, and RNA interference for treating GJB2-related hearing loss.

## Abstract

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.