Most common genetic cause of ARNSHL. Enter the two GJB2 allele results from the laboratory report. Common variants: c.35delG, c.167delT, c.235delC, c.71G>A, p.V37I.
Interpreting GJB2 (Connexin 26, CX26) variant results in patients with sensorineural hearing loss (SNHL).
Most common genetic cause of ARNSHL (Autosomal Recessive Non-Syndromic Hearing Loss) — accounts for ~50% of inherited SNHL in European and Jewish Ashkenazi populations.
Newborn hearing screening follow-up — after ABR/OAE failure, GJB2 is first-tier genetic test.
Critical for cochlear implant candidacy assessment — GJB2-related SNHL has excellent CI outcomes.
Section 2
Formula & Logic
Common Pathogenic Variants by Population
Variant
Populations
Carrier Frequency
c.35delG (p.Gly12ValfsTer2)
European, Middle Eastern
~1/31 Europeans
c.167delT (p.Ile56SerfsTer2)
Ashkenazi Jewish
~1/12 Ashkenazi
c.235delC (p.Leu79CysfsTer3)
East Asian
High frequency in Japan, China, Korea
p.W24X (c.71G>A)
Indian, Asian
Variable
p.V37I (c.109G>A)
Southeast Asian
May cause mild/moderate HL (reduced penetrance)
Inheritance Pattern and Interpretation
GJB2 ARNSHL (DFNB1) is autosomal recessive — two pathogenic alleles required to cause hearing loss.
Biallelic pathogenic variants confirm GJB2 as cause of hearing loss.
Monoallelic pathogenic variant (heterozygous): Carrier status — hearing loss may still have GJB2 contribution if second allele is a large deletion (GJB6/del[GJB6-D13S1830]) — must co-test GJB6.
Biallelic p.V37I: Reduced penetrance — associated with mild to moderate fluctuating hearing loss, not severe/profound SNHL.
Hearing Loss Phenotype in Biallelic Pathogenic GJB2
Genotype
Typical Severity
35delG/35delG (homozygous)
Severe to Profound
35delG/other truncating variant
Severe to Profound
35delG/p.V37I
Mild to Moderate
Two p.V37I alleles
Mild (reduced penetrance)
Section 3
Pearls/Pitfalls
Key Pearls
GJB2 SNHL is non-progressive in most cases — unlike many other genetic causes of hearing loss; this is important for counselling.
Cochlear implant outcomes in GJB2/DFNB1 are among the best of any genetic hearing loss cause — excellent auditory nerve preservation.
Check GJB6 deletions if only one GJB2 pathogenic variant found — GJB6 large deletions act as a "second hit" in ~50% of monoallelic GJB2 cases.
GJB2 hearing loss is non-syndromic — no associated systemic features. If syndromic features present, consider other diagnoses (Usher, Pendred, Jervell & Lange-Nielsen).
Section 4
Next Steps
Clinical Actions
01
Biallelic pathogenic variants confirmed: Genetic counselling; early fitting of hearing aids; cochlear implant assessment if severe/profound; developmental and speech-language therapy.
02
Single pathogenic variant: Complete with GJB6 deletion testing; if second hit found = DFNB1 confirmed.
03
Reproductive counselling: Parents who are both GJB2 heterozygotes have 25% risk of affected child per pregnancy; offer PGT-M.
04
Siblings: Offer targeted carrier testing for identified familial variants; siblings of biallelic cases have 2/3 probability of being carriers.
Section 5
Evidence Appraisal
Primary Reference
Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans
Zelante L et al. • Human Molecular Genetics. 1997;6(9): 1605–1609
Section 6
Literature
Discovery of GJB2/CX26 in ARNSHL
GJB2 was identified as the causative gene for DFNB1 (Autosomal Recessive Non-Syndromic Hearing Loss type 1) by Gasparini, Zelante, and colleagues at IRCCS Burlo Garofolo, Trieste, Italy, published in Human Molecular Genetics in 1997. Separately, Kelsell et al. (Nature 1997) identified GJB2 mutations in autosomal dominant SNHL (DFNA3), establishing connexin-26's dual role in dominant and recessive hearing loss.
Clinical Genomics Impact
GJB2 testing rapidly became the first reflex molecular test in hearing loss genetics because of its very high prevalence, single-gene testing feasibility, and immediate clinical actionability. The high carrier frequency of c.35delG in Europeans (~1/31) makes GJB2 one of the most common Mendelian disease alleles in European populations. Universal newborn hearing screening programmes now incorporate GJB2 in many national genetics frameworks.
