Abstract
In a consanguineous Turkish family diagnosed with autosomal recessive nonsyndromic hearing impairment (arNSHI), a homozygous region of 47.4 Mb was shared by the two affected siblings on chromosome 6p21.1-q15. This region contains 247 genes including the known deafness gene MYO6. No pathogenic variants were found in MYO6, neither with sequence analysis of the coding region and splice sites nor with mRNA analysis. Subsequent candidate gene evaluation revealed CLIC5 as an excellent candidate gene. The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction. Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss. Further analysis of CLIC5 in 213 arNSHI patients from mostly Dutch and Spanish origin did not reveal any additional pathogenic variants. CLIC5 mutations are thus not a common cause of arNSHI in these populations. The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade. Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction. Although we demonstrate that CLIC5 is expressed in many other human tissues, no additional symptoms were observed in these patients. In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin.
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Acknowledgements
We are grateful to the family for their participation in this study. We thank Saskia van der Velde-Visser, Marloes Steehouwer and Irene Janssen for excellent technical assistance, Ersan Kalay for providing Turkish control DNA samples, Arjan de Brouwer for his contribution to the NMD analysis and Rob Collin for SNP-array analysis. This work was financially supported by grants from the Heinsius Houbolt Foundation (to HK), The Oticon Foundation (09-3742, to HK), ZorgOnderzoek Nederland/Medische Wetenschappen (40-00812-98-09047, to HK, 90700388 to RJEP and 016.136.088 to MS), the Netherlands Genomics Initiative (40-41009-98-9073, to MS) and Instituto de Salud Carlos III (FIS PI11/00612, to IdC).
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Seco, C., Oonk, A., Domínguez-Ruiz, M. et al. Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet 23, 189–194 (2015). https://doi.org/10.1038/ejhg.2014.83
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DOI: https://doi.org/10.1038/ejhg.2014.83
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