Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study

Abstract

ObjectivesTo determine the carrier rate of the GJB2 mutation c.35delG and c.101T>C in a UK population study; to determine whether carriers of the mutation had worse hearing or otoacoustic emissions compared to non-carriers.DesignProspective cohort study.SettingUniversity of Bristol, UK.ParticipantsChildren in the Avon Longitudinal Study of Parents and Children. 9202 were successfully genotyped for the c.35delG mutation and c.101>T and classified as either carriers or non-carriers.Outcome measuresHearing thresholds at age 7, 9 and 11 years and otoacoustic emissions at age 9 and 11.ResultsThe carrier frequency of the c.35delG mutation was 1.36% (95% CI 1.13 to 1.62) and c.101T>C was 2.69% (95% CI 2.37 to 3.05). Carriers of c.35delG and c.101T>C had worse hearing than non-carriers at the extra-high frequency of 16 kHz. The mean difference in hearing at age 7 for the c.35delG mutation was 8.53 dB (95% CI 2.99, 14.07) and 12.57 dB at age 9 (95% CI 8.10, 17.04). The mean difference for c.101T>C at age 7 was 3.25 dB (95% CI −0.25 to 6.75) and 7.61 dB (95% CI 4.26 to 10.96) at age 9. Otoacoustic emissions were smaller in the c.35delG mutation carrier group: at 4 kHz the mean difference was −4.95 dB (95% CI −6.70 to −3.21) at age 9 and −3.94 dB (95% CI −5.78 to −2.10) at age 11. There was weak evidence for differences in otoacoustic emissions amplitude for c.101T>C carriers.ConclusionCarriers of the c.35delG mutation and c.101T>C have worse extra-high-frequency hearing than non-carriers. This may be a predictor for changes in lower-frequency hearing in adulthood. The milder effects observed in carriers of c.101T>C are in keeping with its classification as a mutation causing mild/moderate hearing loss in homozygosity or compound heterozygosity.

EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus

“…If the mutation had no specific influence on the phenotype, this would have resulted in a variety of degrees of hearing loss. Moreover, the high prevalence of this variant in the general Caucasian population (carrier rate of 1/37–1/43) 11, 14, 52 and its under-representation in several cohorts with profound deafness, supports its role as a hypomorphic allele rather than a mutation responsible for severe to profound hearing loss. Therefore, if p.(Met34Thr) is present in homozygosity, or with another pathogenic mutation in a patient with mild hearing loss, it is likely to be causative; if the hearing loss is profound however, another cause should be considered.…”

“…In Caucasians, the c.35delG is the most frequent mutation, comprising 70% of alleles in some populations, with a carrier rate of 1–3% in the general population. 7, 10, 11, 12, 13, 14 The c.167delT mutation is the most common mutation in the Ashkenazi Jewish population, 15, 16 c.235delC is found more frequently in the Japanese populations, 17 and p.Trp24* in the Indian, Bangladeshi, Romany, and Slovak populations as well as others. 18, 19, 20, 21, 22 The splice mutation c.−23+1G>A is found in several populations (including Caucasian, Bangladeshi, Egyptian, Algerian, Czech, Turkish, Mongolian, and Chinese).…”

Prevalence of Deafness‐Associated Connexin‐26 (GJB2) and Connexin‐30 (GJB6) Pathogenic Alleles in a Large Patient Cohort from Eastern Sicily

“…Molecular screening for GJB2 variant alleles usually reveals the etiology of deafness and recurrence risks in a high proportion of NSHL cases (Denoyelle et al., ; Lucotte & Diéterlen, ; Petersen & Willems, ; Hall et al., ). In particular, mutation of GJB2 has been reported to be the predominant cause of autosomal‐recessive NSHL in most populations worldwide (Rabionet et al., ; Putcha et al., ).…”

Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in pendred syndrome/enlarged vestibular aqueducts

“…1 in 8). Even if those with variants of unknown significance are excluded, the heterozygote carriership rate for SLC26A4 mutations would be almost 4 times that for GJB2, the commonest form of inherited deafness [40]. This suggests that heterozygosity for SLC26A4 mutations is important in the aetiology of the hearing loss in these patients.…”