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For many years, hearing loss has been an area which has attracted the interest of clinical and academic geneticists. Genetic testing for severe-profound hearing loss is now commonplace in many healthcare systems. Understanding the genetics of hearing loss has improved our ability to give a prognosis of hearing loss, help identify important comorbidities and, in some cases, counsel parents about the possibility of deafness in future offspring. However, we are on the verge of clinical trials of gene therapies for specific genetic causes of hearing loss. Due to its high prevalence and discrete pathological impact, one of the principal targets for gene therapy will be GJB2 hearing loss. The GJB2 gene codes for the Connexin 26 gap junction protein – which is important in communication between adjacent cells in the cochlea. Articles which expand our understanding of GJB2 hearing loss are important, as they provide a basis with which we can make future decisions – both clinical and academic. One of the main areas to be investigated is the relationship between genotype and phenotype. It is recognised that there may be trends towards severity and onset of hearing loss with particular GJB2 mutations, however several variants display wide phenotypic variability. The reasons for this are unclear – no modifier genes have been identified. This study identified siblings who both had homozygous mutations of GJB2 and, in particular, one specific mutation (NM_004004.5(GJB2):c.235delC). Sixteen sibling dyads (including one dizygotic dyad) were identified from a database of 414 individuals with GJB2-related hearing loss. One pair of monozygotic twins were excluded from the analysis and, clearly, whilst two cases would be insufficient to provide a meaningful comparison group, their inclusion would have been interesting – particularly if there was an unexplained disparity between their hearing thresholds. The patterns of hearing loss closely correlated in 11 dyads but, despite their similar genetics and environmental exposures, the hearing loss was significantly different in five. When we can determine the reasons for these differences, we will be another step closer to a better treatment for this form of hearing loss.

Investigation of the hearing levels of siblings affected by a single GJB2 variant: Possibility of genetic modifiers.
Hosoya M, Fujioka M, Nara K, et al.
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Robert Nash

BM BCh, MA(Oxon), MRCS, MA, DOHNS, FRCS (ORL-HNS), Great Ormond Street Hospital, London, UK.

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