Connexin 26 (GJB2 Gene) Defect
Defects in the GJB2 gene, which encodes the connexin 26 protein, are responsible for more than half of genetic cases of profound sensorineural hearing loss in children in the United States. 1
Molecular 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, 2 The GJB2 gene, along with the closely related GJB6 gene, comprises the DFNB1 locus, which represents the single most important genetic cause of childhood deafness. 2
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. 2 The most common pathogenic mutations vary by ethnicity:
- 35delG (also called 30-35insG) is the most prevalent mutation in Caucasian populations, accounting for approximately 40% of pathogenic mutations 2, 3
- 167delT (also called 59delT) is common in Ashkenazi Jewish populations, with a carrier rate of about 4% 3, 4
- Other mutations predominate in Asian and other ethnic groups 2
Clinical Phenotype
GJB2-related hearing loss is typically sensorineural, bilateral, present at birth, and nonprogressive, ranging from mild to profound severity. 2 However, important variations exist:
- Progressive or later-onset hearing loss can occur, particularly with truncating variants 2, 5
- High frequency hearing loss (4000-8000 Hz) is a characteristic feature in children with molecularly diagnosed connexin 26 hearing impairment 6
- Sudden hearing loss has been reported in some families with GJB2 mutations 5
- The hearing loss is nonsyndromic and accompanied by normal vision, vestibular responses, and no malformations of the inner ear detectable by imaging 4
Diagnostic Approach
For children with nonsyndromic sensorineural hearing loss, GJB2 mutation screening by sequence analysis should be performed as the first-line genetic test. 2 The specific algorithm depends on family history:
- Simplex cases (isolated cases): Perform CMV testing first, then proceed to GJB2 sequencing 2
- Multiplex cases (multiple affected family members): Proceed directly to connexin 26 testing without delay 2
Genetic testing should include evaluation for GJB2, GJB6, GJB3, SLC26A4, and mitochondrial genes, as these account for the majority of genetic hearing loss cases. 7
Critical Clinical Pitfall
A negative GJB2 mutation screen does NOT exclude genetic etiology, as emphasized by the American College of Medical Genetics and Genomics. 2 At least 50% of congenital hearing loss is hereditary, with nearly 600 syndromes and 125 genes associated with hearing loss identified. 8 Some children with high frequency hearing loss may have a mutation in only one connexin 26 allele, suggesting connexin 26 involvement even without two identified mutations. 6
Clinical Significance
The carrier rate for GJB2 mutations is approximately 3% in American and European populations—similar to that for cystic fibrosis—making this the most common genetic cause of childhood hearing loss. 4 The relative ease of diagnosis by genetic testing permits early identification of children with GJB2/DFNB1 hearing loss, ensuring that hearing-impaired children and their parents receive proper medical, audiologic, genetic, and educational counseling. 4