Natural history and phenotype-genotype correlations in GJB2-related hearing loss: a systematic and comprehensive...

GJB2-related hearing loss is the most common type of hereditary hearing loss worldwide. However, its complex inheritance patterns, diverse phenotypic manifestations, and population-specific variant spectrum present significant challenges for both clinical practice and research. This review synthesizes evidence from 215 studies (7142 individuals) to quantitatively analyze the natural history and genotype-phenotype correlations across different inheritance patterns, including recessive, dominant, and digenic forms. Among V37I, the V37I/NT genotype is associated with a high proportion of mild-to-moderate hearing loss (84.15%), and the V37I/T genotype shows a flatter configuration than V37I/V37I. An analysis of 178 syndromic cases reveals complex phenotypes involving both the skin and auditory system, characterized by early-onset and severe hearing loss, with clear genotype-phenotype correlations for specific variants. We also summarize genomic and epigenetic mechanisms contributing to phenotypic severity. With a focus on clinical translation, we review the trajectory of GJB2 gene therapy research, from foundational animal studies to innovative therapeutic strategies approaching clinical application. By evaluating the natural history and genotype-specific auditory profiles, this work provides a practical evidence base to guide prognosis, genetic counseling, and crucially, the design of upcoming clinical trials, including patient selection and efficacy assessment. This review is registered with PROSPERO (CRD420251243620).