Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5

Eur J Hum Genet. 2015 Feb;23(2):189-94. doi: 10.1038/ejhg.2014.83.

Celia Zazo Seco ¹, Anne M M Oonk ², María Domínguez-Ruiz ³, Jos M T Draaisma ⁴, Marta Gandía ³, Jaap Oostrik ¹, Kornelia Neveling ⁵, Henricus P M Kunst ², Lies H Hoefsloot ⁶, Ignacio del Castillo ⁷, Ronald J E Pennings ², Hannie Kremer ⁸, Ronald J C Admiraal ², Margit Schraders ¹

Affiliations

1 1] Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands [2] Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands [3] Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
2 1] Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
3 1] Servicio de Genética, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
4 Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands.
5 1] Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands [2] Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands.
6 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
7 Servicio de Genética, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.
8 1] Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands [2] Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands [3] Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands [4] Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

PMID: 24781754 DOI: 10.1038/ejhg.2014.83

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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