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1.  Prevalence and audiological features in carriers of GJB2 mutations, c.35delG and c.101T>C (p.M34T), in a UK population study 
BMJ Open  2012;2(4):e001238.
Objectives
To 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.
Design
Prospective cohort study.
Setting
University of Bristol, UK.
Participants
Children 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 measures
Hearing thresholds at age 7, 9 and 11 years and otoacoustic emissions at age 9 and 11.
Results
The 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.
Conclusion
Carriers 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.
doi:10.1136/bmjopen-2012-001238
PMCID: PMC3449272  PMID: 22855627
Otolaryngology; Audiology; Genetics; Otolaryngology; Paediatric otolaryngology
2.  Hearing in 44–45 year olds with m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced deafness: a population based cohort study 
BMJ Open  2012;2(1):e000411.
Background
The mitochondrial DNA mutation m.1555A>G predisposes to permanent idiosyncratic aminoglycoside-induced deafness that is independent of dose. Research suggests that in some families, m.1555A>G may cause non-syndromic deafness, without aminoglycoside exposure, as well as reduced hearing thresholds with age (age-related hearing loss).
Objectives
To determine whether adults with m.1555A>G have impaired hearing, a factor that would inform the cost–benefit argument for genetic testing prior to aminoglycoside administration.
Design
Population-based cohort study.
Setting
UK.
Participants
Individuals from the British 1958 birth cohort.
Measurements
Hearing thresholds at 1 and 4 kHz at age 44–45 years; m.1555A>G genotyping.
Results
19 of 7350 individuals successfully genotyped had the m.1555A>G mutation, giving a prevalence of 0.26% (95% CI 0.14% to 0.38%) or 1 in 385 (95% CI 1 in 714 to 1 in 263). There was no significant difference in hearing thresholds between those with and without the mutation. Single-nucleotide polymorphism analysis indicated that the mutation has arisen on a number of different mitochondrial haplogroups.
Limitations
No data were collected on aminoglycoside exposure. For three subjects, hearing thresholds could not be predicted because information required for modelling was missing.
Conclusions
In this cohort, hearing in those with m.1555A>G is not significantly different from the general population and appears to be preserved at least until 44–45 years of age. Unbiased ascertainment of mutation carriers provides no evidence that this mutation alone causes non-syndromic hearing impairment in the UK. The findings lend weight to arguments for genetic testing for this mutation prior to aminoglycoside administration, as hearing in susceptible individuals is expected to be preserved well into adult life. Since global use of aminoglycosides is likely to increase, development of a rapid test is a priority.
Article summary
Article focus
Individuals who have the m.1555A>G mutation are exquisitely sensitive to rapid-onset hearing loss after receiving aminoglycosides at normal therapeutic levels.
We sought to determine whether a cohort of mature individuals with the m.1555A>G mutation have hearing loss by their mid-40s because the mutation has been reported to cause later-onset less severe hearing loss in people who have never been exposed to aminoglycosides. We wished to determine whether genetic screening prior to aminoglycoside administration is justified.
Key messages
This study demonstrates the prevalence of m.1555A>G to be 1 in 385 (95% CI 1 in 714 to 1 in 263) in the 1958 British birth cohort, confirming that this mutation occurs frequently in Caucasian populations.
The hearing of individuals with the m.1555A>G mutation is no different to that of the general population at age 44–45 years, in contrast to previous reports which suggested that hearing decreases with age in people with m.1555A>G; any such effect is not large and likely to be subject to previous ascertainment bias.
These findings lend weight to the argument for genetic testing for the m.1555A>G mutation prior to aminoglycoside administration in order to prevent avoidable hearing loss.
Strengths and limitations of this study
Hearing data have been collected prospectively, which avoids some of the biases inherent in studies related to deafness and hearing loss.
A potential limitation of the study was that data on aminoglycoside exposure were not collected.
doi:10.1136/bmjopen-2011-000411
PMCID: PMC3253422  PMID: 22223843

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