What protein is responsible for sensorineural (SNHL) hearing loss in young patients and children?

Connexin 26 (GJB2 Gene Product) is the Primary Protein Responsible for Sensorineural Hearing Loss in Young Patients and Children

The gap junction protein connexin 26, encoded by the GJB2 gene, accounts for approximately 50% of all autosomal recessive nonsyndromic sensorineural hearing loss and 15-40% of all deaf individuals across diverse populations, making it the single most important genetic cause of childhood deafness. 1, 2

Primary Protein: Connexin 26

Molecular Function 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 2
• The GJB2 gene, along with the closely related GJB6 gene (encoding connexin 30), comprises the DFNB1 locus 1, 2
• More than 150 deafness-causing variants have been identified in GJB2, though a few common mutations (particularly 35delG in Caucasian populations) account for the majority of cases 1, 2

Clinical Phenotype

• GJB2-related hearing loss is typically sensorineural, bilateral, present at birth, and nonprogressive, ranging from mild to profound severity 1, 2
• Progressive or later-onset hearing loss can occur, particularly with truncating variants 1, 2
• The hearing loss is usually congenital and detected through newborn screening programs 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 2
• Testing for common GJB2/GJB6 mutations in pediatric patients has considerable diagnostic value (14% yield in children vs only 1% in adults) 3
• The 35delG homozygous state is the most common pathogenic genotype (54% of identified cases) 3

Critical Diagnostic Pitfall

• A negative GJB2 mutation screen does NOT exclude genetic etiology 2
• Other genetic causes must be considered when GJB2 testing is negative 1

Secondary Protein: Otoferlin (OTOF Gene Product)

Role in Pediatric Hearing Loss

• Otoferlin, a calcium-binding protein encoded by the OTOF gene, is responsible for 1-8% of congenital, nonsyndromic hearing loss 4
• Otoferlin is the leading cause of auditory neuropathy spectrum disorders (ANSD) in children 4, 5

Clinical Characteristics

• Most patients display severe-to-profound hearing loss with prelingual onset 4
• 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss 4, 6
• Otoacoustic emissions may be present (spared) in OTOF-related hearing loss, distinguishing it from other causes 6

Diagnostic Considerations

• Non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes 4
• All children with ANSD should undergo genetic testing for OTOF pathogenic variants to identify candidacy for emerging gene therapy trials 5

Testing Algorithm for Young Patients

First-Line Testing

1. Screen for GJB2 and GJB6 mutations in all children with nonsyndromic sensorineural hearing loss 1, 2, 3
2. Test for congenital cytomegalovirus (CMV) in simplex cases before proceeding to genetic testing 2
3. Proceed directly to connexin 26 testing in multiplex cases (positive family history) 2

Second-Line Testing

• If GJB2/GJB6 testing is negative and ANSD is present, test for OTOF mutations 4, 5
• Consider comprehensive hearing loss gene panel testing, including SLC26A4 and mitochondrial genes 7
• Mitochondrial DNA testing (MT-RNR1, MT-TS1) should be considered in adults but has very low yield in pediatric populations 1, 3

Population-Specific Considerations

• The most common pathogenic mutations vary by ethnicity: 35delG is prevalent in Caucasian populations, while other mutations predominate in Asian and other ethnic groups 2
• Mitochondrial mutations have slightly higher incidence in Spain and East Asian countries 1

Clinical Management Implications

Immediate Actions

• Amplification devices must be fitted within 1 month of confirmed diagnosis 7
• Early intervention services must begin no later than 6 months of age 7
• Refer to pediatric otolaryngologist and multidisciplinary hearing healthcare team immediately 7

Prognostic Value of Genetic Diagnosis

• Genetic diagnosis influences prognosis and management, as certain mutations (particularly OTOF variants) are associated with progressive loss requiring closer monitoring 7, 4
• Families should receive genetic counseling regarding etiology, prognosis, associated disorders, and recurrence risk 7