Abstract
Pathogenic variant in COCH are a known cause of DFNA9 autosomal dominant progressive hearing loss and vestibular dysfunction with adult onset. Hitherto, only dominant nonsynonymous variants and in-frame deletions with a presumed dominant negative or gain-of-function effect have been described. Here, we describe two brothers with congenital prelingual deafness and a homozygous nonsense c.292C>T(p.Arg98*) COCH variant, suggesting a loss-of-function effect. Vestibular dysfunction starting in the first decade was observed in the older patient. The heterozygous parents and sibling have normal hearing and vestibular function, except for the mother, who shows vestibular hyporeflexia and abnormal smooth pursuit tests, most likely due to concomitant disease. This is the first report of autosomal recessive inheritance of cochlea-vestibular dysfunction caused by a pathogenic variant in the COCH gene. An earlier onset of hearing impairment and vestibular dysfunction compared to the dominant hearing loss causing COCH variants is observed.
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References
Shearer AE, Hildebrand MS, Smith RJH. Hereditary Hearing Loss and Deafness Overview.In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors.GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.1999 Feb 14 [updated 2017 Jul 27]. NCBI Bookshelf:https://www.ncbi.nlm.nih.gov/books/NBK1434.
Robertson NG, Khetarpal U, Gutierrez-Espelata GA, Bieber FR, Morton CC. Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening. Genomics. 1994;23:42–50.
Bae SH, Robertson NG, Cho HJ, et al. Identification of pathogenic mechanisms of COCH mutations, abolished cochlin secretion, and intracellular aggregate formation: genotype-phenotype correlations in DFNA9 deafness and vestibular disorder. Hum Mutat. 2014;35:1506–13.
Jung J, Choi JY, Kim HS, et al. Novel COCH p.V123E mutation, causative of DFNA9 sensorineural hearing loss and vestibular disorder, shows impaired cochlin post-translational cleavage and secretion. Human Mut. 2015;36:1168–75.
Tsukada K, Ichinose A, Miyagawa M, et al. Detailed hearing and vestibular profiles in the patients with COCH mutations. Ann Otol Rhinol Laryngol. 2015;124:100S-110S
Hildebrand MS, Gandolfo L, Shearer AE, et al. A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss. Laryngoscope. 2010;120:2489–93.
Picciani R, Desai K, Guduric-Fuchs J, et al. Cochlin in the eye: functional implications. Prog Retin Eye Res. 2007;26:453–69.
Usami SI, Takahashi K, Yuge I, et al. Mutations in the COCH gene are a frequent cause of autosomal dominant progressive cochleo-vestibular dysfunction, but not of Meniere’s disease. Eur J Hum Genet. 2003;11:744–8.
Janssens de Varebeke SP, Termote B, Van Camp G, et al. Focal sclerosis of semicircular canals with severe DFNA9 hearing impairment caused by a P51S COCH-mutation: is there a link? Otol Neurotol. 2014;35:1077–86.
Robertson NG, Resendes BL, Lin JS, et al. Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9. Am J Hum Genet. 2001;69:348.
Bom SJH, Kemperman MH, De Kok YJM, et al. Progressive Cochleovestibular Impairment Caused by a Point Mutation in the COCH Gene at DFNA9. Laryngoscope. 1999;109:1525–30.
Bischoff MLC, Huygen LMP, Kemperman HM, et al. Vestibular deterioration precedes hearing deterioration in the P51S COCH Mutation (DFNA9): an analysis in 74 mutation carriers. Otol Neurotol. 2005;26:918–25.
Yao J, Py BF, Bao J et al. Role of protein misfolding in DFNA9 hearing loss. J Biol Chem. 2010; 285, 14909-19.
Cho HJ, Park HJ, Trexler M, et al. A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. J Mol Med (Berl). 2012;90:1321–31.
Makishima T, Rodriguez CI, Robertson NG, et al. Targeted disruption of mouse Coch provides functional evidence that DFNA9 hearing loss is not a COCH haploinsufficiency disorder. Hum Genet. 2005;118:29–34.
Gao J, Xue J, Chen L, et al. Whole exome sequencing identifies a novel DFNA9 mutation, C162Y. Clin Genet. 2013;83:477–81. 5
Jones SM, Robertson NG, Given S, et al. Hearing and vestibular deficits in the coch(−/−) null mouse model: comparison to the coch(G88E/G88E) mouse and to DFNA9 hearing and balance disorder. Hear Res. 2011;272:42–8.
Masuda M, Mutai H, Arimoto Y, et al. A novel frameshift variant of COCH supports the hypothesis that haploinsufficiency is not a cause of autosomal dominant nonsyndromic deafness 9. Biochem Biophys Res Commun. 2015;469:270–4.
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JanssensdeVarebeke, S.P.F., Van Camp, G., Peeters, N. et al. Bi-allelic inactivating variants in the COCH gene cause autosomal recessive prelingual hearing impairment. Eur J Hum Genet 26, 587–591 (2018). https://doi.org/10.1038/s41431-017-0066-2
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DOI: https://doi.org/10.1038/s41431-017-0066-2
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