rs35887543 — GJB2 c.235delC

GJB2 c.235delC — The East Asian Deafness Founder Mutation

The cochlea converts sound waves into electrical nerve signals through an exquisitely precise ionic mechanism. Connexin 26, encoded by GJB2¹¹ Connexin 26, encoded by GJB2
Gap Junction Protein Beta-2; the most common gene for hereditary non-syndromic hearing loss worldwide forms the gap junction channels in cochlear support cells that maintain this mechanism. The c.235delC frameshift deletion — rs35887543 in the GeneOps database — eliminates connexin 26 function entirely. It is the dominant hereditary deafness allele across East Asia, carried by roughly 1 in 100 Chinese, Japanese, and Korean individuals, and is the most important single genetic cause of severe prelingual hearing loss in these populations.

Unlike the V37I missense variant, which partially reduces gap junction activity and causes mild-to-moderate hearing loss, c.235delC is a null allele: it abolishes protein function completely. Two copies produce severe-to-profound congenital sensorineural hearing loss in the vast majority of cases. The mutation arose from a single ancestral founder in East Asia, explaining its ethnic specificity and absence in European and African populations.

The Mechanism

The c.235delC deletion removes a cytosine at position 235 of the GJB2 coding sequence (on the coding strand; the gene lies on the minus strand of chromosome 13). This one-base frameshift shifts the reading frame beginning at codon 79, generating a premature stop codon three positions later: p.Leu79Cysfs*3²² p.Leu79Cysfs*3
The truncated protein is only 81 amino acids long — less than one-third the normal 226 amino acids.

The truncated peptide lacks the second through fourth transmembrane domains, the cytoplasmic loop, and the C-terminal tail — structures required for hexamer assembly and membrane targeting. Nonsense-mediated mRNA decay³³ Nonsense-mediated mRNA decay
A cellular pathway that degrades transcripts with premature stop codons, preventing synthesis of potentially dominant-negative truncated proteins likely eliminates most of the aberrant mRNA. No functional connexin 26 reaches the cell membrane in homozygotes. The result is the same functional null state as c.35delG in Europeans: complete loss of cochlear gap junction channels, failure of potassium ion recycling through the supporting cell network, collapse of the endocochlear potential, and hair cell death.

The Evidence

The East Asian specificity and founder effect of c.235delC were established by Yan et al. — Human Genetics 2003, PMID 14505035⁴⁴ Yan et al. — Human Genetics 2003, PMID 14505035, which demonstrated significant linkage disequilibrium between the mutation and five flanking markers, and its presence exclusively in East Asian populations absent from Caucasians — consistent with a single ancestral origin after the divergence of East Asian and European lineages.

The mutation burden in deaf populations across China was quantified by Chan et al. — Genetics in Medicine 2007, PMID 17505205⁵⁵ Chan et al. — Genetics in Medicine 2007, PMID 17505205: among 3,004 nonsyndromic hearing-impaired Chinese patients, 16.3% carried at least one c.235delC allele, with 7.8% homozygous and 8.5% heterozygous. The carrier frequency in healthy Chinese controls was approximately 1.4%.

The risk conferred by homozygous c.235delC was quantified by Dai et al. — Journal of Translational Medicine 2012, PMID 22747691⁶⁶ Dai et al. — Journal of Translational Medicine 2012, PMID 22747691, a meta-analysis of 36 studies covering 13,217 cases and 6,521 controls: the overall odds ratio for non-syndromic hearing loss was 7.9 (95% CI 4.77–13.11), rising to 12.05 (95% CI 8.33–17.44) in the East and Southeast Asian subgroup. No significant association was found in European or Oceanian populations, confirming the East Asian specificity.

Phenotypic characterisation of 244 patients with homozygous c.235delC by Guo et al. — Neural Plasticity 2020, PMID 32802038⁷⁷ Guo et al. — Neural Plasticity 2020, PMID 32802038 found that 71.9% had profound hearing loss (>90 dB HL) and 14.3% severe loss (70–90 dB HL), with 63.9% showing bilateral asymmetry in severity or audiogram shape. A complementary Frontiers in Cell and Developmental Biology 2021 study (PMC7953049)⁸⁸ Frontiers in Cell and Developmental Biology 2021 study (PMC7953049) of 295 homozygotes identified a small but important phenotypic minority: 1.36% had post-lingual onset and 2.71% had prelingual moderate-only hearing loss, suggesting that unidentified modifier genes can partially compensate for c.235delC null status.

Genotype-phenotype data from the largest international GJB2 consortium — Snoeckx et al. — 1,531 biallelic cases, PMID 16380907⁹⁹ Snoeckx et al. — 1,531 biallelic cases, PMID 16380907 — confirmed that biallelic truncating mutations (including c.235delC) produce significantly more severe hearing loss than non-truncating genotypes (p<0.0001), with profound loss in 64% and severe in 25% of truncating homozygotes.

A notable edge case was reported by Xia et al. — Genetics and Molecular Biology 2019, PMID 30816908¹⁰¹⁰ Xia et al. — Genetics and Molecular Biology 2019, PMID 30816908: a patient with homozygous c.235delC presented with auditory neuropathy spectrum disorder (ANSD) features — absent auditory brainstem responses with some preserved otoacoustic emissions — representing the first documented ANSD presentation for this genotype. This case expands the phenotypic spectrum and underscores the importance of comprehensive audiological evaluation beyond simple pure-tone thresholds.

Practical Actions

For the vast majority of homozygous c.235delC individuals (DD genotype), hearing loss is severe to profound and presents in early childhood or at birth. The most impactful intervention is early cochlear implantation: GJB2-related deafness leaves the auditory nerve structurally intact, making CI outcomes among the best of any deafness etiology. Takahashi et al. — PMID 21292415¹¹¹¹ Takahashi et al. — PMID 21292415 confirmed threshold improvement after CI in all 16 homozygous c.235delC recipients studied.

The 1-3-6 milestone framework from the Joint Committee on Infant Hearing — hearing screening completed by one month, diagnosis confirmed by three months, early intervention started by six months — is the clinical standard that maximises speech and language development. Early genetic diagnosis via GJB2 sequencing can accelerate this timeline by providing the aetiology before audiology confirms severity.

Single heterozygous carriers (DI genotype) have normal hearing; their significance is exclusively reproductive. When two carriers conceive a child, each pregnancy has a 25% chance of biallelic c.235delC and severe-to-profound hearing loss.

Interactions

The most clinically significant compound heterozygous configuration in East Asian populations is c.235delC in trans with V37I (rs72474224). Because V37I is a partial loss-of-function allele while c.235delC is a complete null, compound heterozygotes typically show hearing loss of intermediate severity — milder than c.235delC homozygotes but more significant than V37I homozygotes. Some c.235delC/V37I compound heterozygotes have reportedly presented with borderline-normal audiograms, highlighting the V37I allele's partial preservation of gap junction function.

In East Asian populations with one c.235delC allele and unexplained sensorineural hearing loss, full GJB2 sequencing is essential to identify a second pathogenic allele on the opposite chromosome, including other frameshift variants such as c.167delT (rs80338942), and to test for large GJB6 gene deletions (del(GJB6-D13S1830) and del(GJB6-D13S1854)) that act as pathogenic second alleles for any GJB2 pathogenic variant.