rs80338942 — GJB2 167delT

GJB2 167delT — The Ashkenazi Jewish Founder Allele for Connexin 26 Deafness

The GJB2 gene encodes connexin 26 (Cx26), a gap-junction protein that forms channels between the support cells lining the cochlear duct. These channels maintain the ionic environment that inner hair cells require to convert sound vibrations into electrical nerve signals. The 167delT variant — a deletion of a single thymine at position 167 of the coding sequence — disrupts this system irreversibly. Among Ashkenazi Jews, it is the single most common cause of hereditary nonsyndromic deafness: approximately 1 in 25 Ashkenazi Jewish individuals carries this allele, making it one of the highest-frequency recessive disease alleles in any human population.

Like the European 35delG variant (rs80338939), 167delT is a founder mutation — all copies in the Ashkenazi population trace back to a single ancestral chromosome, as evidenced by the conservation of the surrounding haplotype first demonstrated in the landmark 1998 NEJM study. The mutation is virtually absent outside the Ashkenazi Jewish population, which means its clinical significance is highly population-specific.

The Mechanism

The c.167delT deletion removes a single thymine at nucleotide position 167 of the GJB2 coding sequence. Because GJB2 is transcribed from the minus strand of chromosome 13, this coding-strand thymine deletion appears on the genomic plus strand as deletion of an adenine at position NC_000013.11:g.20189415. The resulting frameshift shifts the reading frame from codon 56 onward, producing a premature stop codon after 26 additional out-of-frame amino acids (p.Leu56Argfs*26). The truncated 81-amino-acid product retains only the first transmembrane domain of connexin 26 and is non-functional; no intact Cx26 protein reaches the membrane.

The cochlear consequence is identical to that of 35delG homozygosity: absence of Cx26 gap junctions between cochlear support cells disrupts potassium recycling, intercellular ATP-calcium signaling during cochlear development, and glucose supply to the sensory epithelium — collectively preventing normal maturation and function of the organ of Corti.

The Evidence

The population genetics of 167delT are exceptionally well-characterized. Morell et al. — GJB2 mutations in Ashkenazi Jewish families with nonsyndromic recessive deafness¹¹ Morell et al. — GJB2 mutations in Ashkenazi Jewish families with nonsyndromic recessive deafness
Prevalence of heterozygosity for 167delT was 4.03% (95% CI 2.5–6.0%); combined carrier rate of 4.76% predicts 1 affected person per 1,765 Ashkenazi Jews. N Engl J Med 1998 established the mutation as the dominant cause of recessive deafness in this population. A subsequent study of 1,012 anonymous Ashkenazi Jewish individuals from the New York metropolitan area²² 1,012 anonymous Ashkenazi Jewish individuals from the New York metropolitan area
Fischel-Ghodsian et al., Am J Med Genet 2000 confirmed a carrier frequency of 3.96% (95% CI 2.75–5.15%). The variant is near-absent in European, East Asian, African, and South Asian populations, consistent with a single Ashkenazi founder event.

Genotype-phenotype data show that biallelic 167delT causes prelingual sensorineural hearing loss with a range of severity that is somewhat broader than 35delG homozygosity. Lerer et al. — Variable phenotypic effect of 167delT in Ashkenazi patients³³ Lerer et al. — Variable phenotypic effect of 167delT in Ashkenazi patients
Biallelic 167delT associated with mild-to-profound hearing loss; some compound heterozygotes (167delT/M34T) were unaffected. Am J Hum Genet 2000 demonstrated that the phenotypic range is wider when 167delT is paired with a non-truncating allele. However, when paired with another truncating allele — including another copy of 167delT or a 35delG — outcomes align with the Snoeckx multicenter study⁴⁴ Snoeckx multicenter study
Truncating homozygotes: 64% profound, 25% severe, 10% moderate. Am J Hum Genet 2005 showing predominantly severe-to-profound loss.

Cochlear implantation outcomes for GJB2-related deafness, including 167delT, are consistently favorable. Lustig et al. — GJB2 mutations and cochlear implant outcomes⁵⁵ Lustig et al. — GJB2 mutations and cochlear implant outcomes
No difference in speech awareness or recognition thresholds between GJB2-related and non-GJB2 cochlear implant recipients. Arch Otolaryngol Head Neck Surg 2004 demonstrated that GJB2 etiology does not impair implant benefit, and early implantation consistently yields excellent speech and language outcomes.

Practical Actions

For carriers (one 167delT allele), the primary implication is reproductive planning. The 1-in-25 Ashkenazi Jewish carrier frequency means that two Ashkenazi Jewish parents have approximately a 1-in-625 chance per pregnancy of having a child with biallelic GJB2 deafness from this variant alone. This risk increases substantially if the partner carries any other GJB2 loss-of-function allele — including 35delG, which is not uncommon in individuals of mixed Ashkenazi/European ancestry. Partner testing and genetic counseling are the principal clinical actions for carriers.

For homozygotes or compound heterozygotes identified at birth — most often through newborn hearing screening — early cochlear implantation is the most impactful intervention. The Joint Committee on Infant Hearing 1-3-6 benchmark applies: hearing screening by one month, diagnosis confirmed by three months, early intervention begun by six months. GJB2 etiology predicts intact auditory nerve function, making cochlear implant candidacy favorable and outcomes reliably excellent.

Interactions

The most important interactions involve 167delT in compound heterozygosity with other GJB2 loss-of-function alleles. In Ashkenazi Jewish individuals, the most clinically relevant compound genotypes are 167delT/35delG (the European frameshift allele, rs80338939) and 167delT/W24X. Both produce deafness equivalent in severity to 167delT homozygosity. Compound 167delT/M34T (rs111033252) is less penetrant: some carriers are unaffected, and this combination may produce milder or no hearing loss.

As with 35delG, compound heterozygosity with a GJB6 deletion [del(GJB6-D13S1830)] causing trans-regulatory disruption of GJB2 expression has been reported in Ashkenazi families, though this combination is less common than in European populations.

In Ashkenazi Jewish individuals with a single identified GJB2 pathogenic variant who are deaf, sequencing of the full GJB2 coding region and testing for large GJB6 deletions should be performed to resolve compound heterozygosity.