rs80338939 — GJB2 35delG

GJB2 35delG — The Leading Genetic Cause of Congenital Deafness in Europeans

The GJB2 gene encodes connexin 26 (Cx26), a gap-junction protein that forms channels between the epithelial support cells and fibrocytes lining the cochlear duct. These channels are essential for maintaining the ionic environment that hair cells need to convert sound vibrations into electrical nerve signals. The 35delG variant — a deletion of a single guanine in a run of six consecutive guanines — disrupts this system completely.

Worldwide, GJB2 mutations account for roughly 50% of genetic nonsyndromic hearing loss. Among Europeans, the 35delG variant alone explains the majority of that burden. In southern European populations, approximately 1 in 35 people carry one copy of this deletion, making it one of the most prevalent disease-causing alleles in the human genome. Two copies cause severe-to-profound congenital deafness in nearly all cases.

The Mechanism

The c.35delG deletion removes one guanine from a homopolymeric run at positions 30–35 of the GJB2 coding sequence. This frameshift shifts the reading frame from codon 12 onward, producing a premature stop codon at position 13 (p.Gly12Valfs*2). The truncated 12-amino-acid peptide lacks all functional domains and is degraded; no connexin 26 protein reaches the membrane.

Gap junctions formed by connexin 26¹¹ Gap junctions formed by connexin 26
Connexin monomers assemble into hexamers called connexons; one connexon from each adjacent cell docks to form a gap junction channel permeable to ions and small molecules up to ~1 kDa in the cochlear support cells are required for at least three functions: recycling potassium ions from the base of hair cells back to the endolymph above them, propagating ATP-calcium intercellular signaling waves during development of the organ of Corti, and supplying glucose to the sensory epithelium. Loss of Cx26 disrupts all three pathways, with current evidence suggesting developmental ATP-calcium signaling failure²² developmental ATP-calcium signaling failure
Without Cx26, Ca2+ waves fail to propagate through Kolliker's organ during embryonic development, disrupting cochlear maturation may be the primary mechanism rather than acute ion recycling failure.

The Evidence

The population genetics of 35delG are among the best characterized of any recessive variant. Gasparini et al. — Genetic Analysis Consortium of GJB2 35delG³³ Gasparini et al. — Genetic Analysis Consortium of GJB2 35delG
Carrier frequency 1 in 35 in southern Europe, 1 in 79 in central/northern Europe; absent in non-European controls. Eur J Hum Genet 2000 established the geographic gradient: the mutation is most prevalent in Mediterranean countries and decreases moving north and east. A later meta-analysis of 23,187 random controls across 5 continents⁴⁴ meta-analysis of 23,187 random controls across 5 continents
Mahdieh & Rabbani, Int J Audiol 2009 confirmed mean carrier rates of 1.89% European, 1.52% American, 0.64% African and Asian.

Genotype-phenotype correlations are well established. Snoeckx et al. — 1,531 individuals with biallelic GJB2 mutations across 16 countries⁵⁵ Snoeckx et al. — 1,531 individuals with biallelic GJB2 mutations across 16 countries
Truncating homozygotes had significantly more severe loss than nontruncating genotypes (p<0.0001). Am J Hum Genet 2005 showed that among 35delG/35delG homozygotes: 64% had profound loss (>90 dB), 25% severe (70–90 dB), and only 10% moderate. Heterozygous carriers — one deletion plus one normal allele — have normal hearing.

Newborn hearing screening reliably detects most, but not all, affected infants. Norris et al. — Universal NBHS follow-up study⁶⁶ Norris et al. — Universal NBHS follow-up study
~3.8% of GJB2-related deafness passes neonatal OAE/ABR screening, with some infants presenting with progressive loss weeks to months later. Ear Hear 2006 documented that late-onset presentations occur and can be missed without genetic testing.

Cochlear implantation outcomes are favorable. Lustig et al. — CI recipients with GJB2 mutations vs. controls⁷⁷ Lustig et al. — CI recipients with GJB2 mutations vs. controls
No difference in speech awareness or recognition thresholds between GJB2-related and non-GJB2 cochlear implant recipients. Arch Otolaryngol Head Neck Surg 2004 found that GJB2 etiology does not impair implant benefit, and early implantation in GJB2 children consistently yields excellent speech and language outcomes.

Practical Actions

For carriers (one 35delG allele), the clinical implications are limited to reproductive planning: carrier couples have a 25% chance per pregnancy of having a deaf child. Genetic counseling before conception, and GJB2 testing of a partner, allows informed family planning decisions. Prenatal or preimplantation diagnosis is available.

For homozygotes identified at birth — most commonly through newborn hearing screening — the most impactful intervention is early cochlear implantation. The recommended timeline from the Joint Committee on Infant Hearing is: hearing screening completed by one month, diagnosis confirmed by three months, and early intervention started by six months. Children implanted early can achieve speech and language development indistinguishable from hearing peers.

Carriers should also be aware that some late-onset presentations exist, and that children who pass newborn hearing screening but have known GJB2 compound heterozygosity should be monitored audiologically.

Interactions

The most clinically important interaction is compound heterozygosity between 35delG and a deletion in the neighboring GJB6 gene. The del(GJB6-D13S1830) deletion removes a shared regulatory region that controls expression of both GJB2 and GJB6 on the same chromosome; 35delG on one allele plus this GJB6 deletion on the other allele produces deafness identical in severity to 35delG homozygosity. In Spain, this digenic combination accounts for approximately half of all deaf GJB2 single-heterozygotes. Testing of both genes is therefore standard practice when a single GJB2 pathogenic variant is found in a deaf proband.

Other GJB2 pathogenic variants — including 167delT (common in Ashkenazi Jews), 235delC (common in East Asians), and W24X (common in South Asians and some African populations) — cause deafness through similar loss-of-function mechanisms when biallelic. Population-matched testing panels are used clinically to capture these population-specific variants.