Connexin 26 (Encoded by GJB2 Gene)
Connexin 26, a gap junction protein encoded by the GJB2 gene, is the protein most commonly responsible for sensorineural hearing loss in children, accounting for 50% of all autosomal recessive nonsyndromic hearing loss and 15-40% of all deaf individuals in various populations. 1
Molecular Basis and Mechanism
Connexin 26 is a gap junction protein of the beta subunit class that functions in cell-to-cell diffusion and recycling of small molecules such as potassium in the inner ear. 1
The GJB2 gene, along with the closely related GJB6 gene (encoding connexin 30), comprises the DFNB1 locus, which represents the single most important genetic cause of childhood deafness. 1
More than 150 different deafness-causing variants have been identified in GJB2, though a few common mutations account for the majority of cases in most populations. 1
Clinical Characteristics
GJB2-related hearing loss is typically sensorineural, bilateral, present at birth, and nonprogressive, ranging from mild to profound severity. 1
High-frequency hearing loss (4000-8000 Hz) is a characteristic audiometric feature in children with molecularly confirmed connexin 26 mutations. 2
Progressive or later-onset hearing loss can occur, particularly with truncating variants. 1
Diagnostic Approach
For children with nonsyndromic sensorineural hearing loss, GJB2 mutation screening by sequence analysis should be performed as the first-line genetic test, as it can avoid expensive and potentially invasive diagnostic procedures when positive. 1
Testing Algorithm:
Simplex cases (isolated cases): Perform CMV testing first, then proceed to GJB2 sequencing. 1
Multiplex cases (affected first-degree relatives): Proceed directly to connexin 26 testing without delay. 1
Both parents deaf: Connexin-related deafness is strongly suspected, as the vast majority of marriages between deaf individuals producing deaf offspring involve GJB2 mutations. 1
Population-Specific Considerations
The most common pathogenic mutations vary by ethnicity, with 35delG being prevalent in Caucasian populations and other mutations predominant in Asian and other ethnic groups. 1
In the German population, GJB2 mutations account for 22% of severe to profound hearing loss cases. 3
Among Indian populations, insertions at nucleotides 30-35 (40% of cases) and deletions at nucleotide 59 (20% of cases) are the most common pathogenic mutations. 4
Critical Clinical Pitfall
A negative GJB2 mutation screen does NOT exclude genetic etiology—this distinction is frequently misunderstood and inadequately conveyed to families. 1 The probability of genetic causation remains substantial even with negative testing, varying based on family history and number of hearing siblings. 1