rs80338942 — GJB2 167delT

The most common GJB2 deafness allele in the Ashkenazi Jewish population (~4% carrier frequency); frameshift deletion eliminates connexin 26 function and causes congenital sensorineural hearing loss in homozygotes or compound heterozygotes

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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.

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

No GJB2 167delT deletion — standard connexin 26 function

You carry two intact copies of the GJB2 gene at the 167delT position. Your connexin 26 protein functions normally in the cochlea. This genotype is found in nearly all non-Ashkenazi individuals worldwide, and in approximately 92% of people of Ashkenazi Jewish descent. Your risk of GJB2-related hearing loss from this specific variant is at general population background level.

DI Carrier Carrier

Carrier of one GJB2 167delT allele — normal hearing, reproductive implications

The 167delT mutation follows autosomal recessive inheritance. One functional GJB2 allele produces enough connexin 26 protein to maintain cochlear gap junction function; carriers are reported to have normal audiometric thresholds in all published literature.

The reproductive risk is population-specific. Among Ashkenazi Jewish individuals, the approximately 4% carrier frequency for 167delT means two Ashkenazi partners have roughly a 1-in-625 chance per pregnancy of having a child with biallelic 167delT/167delT deafness. This risk is higher if the partner carries any GJB2 loss-of-function allele, including 35delG (which is present at ~1–2% in European populations) or W24X. An Ashkenazi Jewish carrier of 167delT with a partner of European ancestry should request full GJB2 panel testing including 35delG.

The 167delT carrier frequency among Ashkenazi Jews (~4%) is substantially higher than the 35delG carrier frequency (~0.73% in Ashkenazi populations), making 167delT the dominant Ashkenazi GJB2 allele and the most important target for GJB2 carrier screening in this population.

DD Homozygous Homozygous

Two GJB2 167delT alleles — no functional connexin 26; congenital sensorineural hearing loss expected

The 167delT/167delT genotype causes nonsyndromic sensorineural hearing loss that is prelingual (present from birth or very early infancy), predominantly non-progressive, and restricted to hearing — there are no associated syndromic features such as vision loss, cardiac involvement, or neurological findings. This distinguishes it from syndromic forms of genetic deafness (Usher syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome).

The phenotypic variability reported for 167delT is slightly broader than for 35delG. Lerer et al. (2000) documented that while most biallelic 167delT individuals have severe-to-profound loss, a subset has moderate loss, and compound heterozygotes with the non-truncating M34T allele may have even milder phenotypes or remain unaffected. For fully truncating genotypes (167delT/167delT or 167delT/35delG), outcomes align with Snoeckx et al. (2005): approximately 64% profound, 25% severe, 10% moderate.

Because connexin 26 is cochlear-restricted and the auditory nerve is intact, cochlear implantation bypasses the defective organ and delivers stimulation directly to functional auditory nerve fibers. GJB2-related deafness — including 167delT — is associated with equal or better cochlear implant outcomes compared to other etiologies. Early implantation before 12 months of age maximizes speech and language development.

Approximately 3–5% of GJB2 homozygotes will pass newborn OAE/ABR screening at birth, so a negative neonatal screen does not exclude GJB2-related hearing loss in a child with a known family history or positive genetic test.