Global GJB2 mutation prevalence in nonsyndromic hearing impairment

This systematic review and meta-analysis synthesized data from 24 countries, encompassing 18,968 patients with nonsyndromic hearing impairment, to determine the global prevalence of GJB2 gene mutations. The primary analysis focused on the overall prevalence of GJB2 mutations and five hotspot variants, providing a comprehensive epidemiological overview for clinicians and genetic counselors.

The overall prevalence of GJB2 mutations was 25.9% (95% CI: 21.7-30.1%), indicating that approximately one in four patients with nonsyndromic hearing loss harbors a pathogenic variant in this gene. This finding underscores the significant role of GJB2 in the etiology of hereditary hearing impairment and supports its inclusion in targeted genetic testing panels.

Among the specific hotspot variants, c.235delC was the most common, with a prevalence of 15.2%, followed by c.35delG at 12.0%. Other notable variants included c.109G>A (7.6%), c.299_300delAT (3.1%), and c.176_191del16 (0.7%). These variants collectively account for a substantial proportion of GJB2-related hearing loss, informing the design of region-specific genetic screening strategies.

Regional analysis revealed significant geographic heterogeneity. The prevalence of GJB2 mutations was highest in the Middle East at 38.5%, suggesting a founder effect or population-specific genetic architecture. In contrast, the prevalence in Africa was 11.1%, highlighting the need for tailored diagnostic approaches based on ancestral background.

The study's practice relevance emphasizes supporting region-specific genetic screening to improve early diagnosis, counseling, and targeted interventions for hereditary hearing loss. For clinicians, these data can guide the selection of genetic tests and inform discussions with patients about the likelihood of identifying a GJB2 mutation.

Limitations of the meta-analysis include potential heterogeneity in study designs and diagnostic criteria across the included studies. The analysis did not assess the functional impact of each variant or correlate genotype with phenotype severity, which are important considerations for clinical management.

In conclusion, this meta-analysis provides robust estimates of GJB2 mutation prevalence in nonsyndromic hearing impairment, with clear regional variations. These findings support the integration of genetic testing into routine care for patients with hearing loss, particularly in regions with high prevalence, to facilitate early intervention and family counseling.