To evaluate the clinical features of Japanese DFNA9 families with mutations of the COCH gene.
Methods:
Mutation screening was performed using targeted next-generation sequencing (NGS) for 63 previously reported deafness genes. The progression of hearing loss and vestibular dysfunction were evaluated by pure-tone audiometry, caloric testing, cVEMP, and computed dynamic posturography.
Results:
We detected 1 reported mutation of p.G88E and 2 novel mutations of p.I372T and p.C542R. The patients with the novel mutations of p.I372T and p.C542R within the vWFA2 domain showed early onset progressive hearing loss, and the patients with the p.G88E mutation showed late onset hearing loss and acute hearing deterioration over a short period. Vestibular symptoms were reported in the patients with p.G88E and p.C542R. Vestibular testing was performed for the family with the p.G88E mutation. Severe vestibular dysfunction was observed in the proband, and the proband’s son showed unilateral semicircular canal dysfunction with mild hearing loss.
Conclusions:
Targeted exon resequencing of selected genes using NGS successfully identified mutations in the relatively rare deafness gene, COCH, in the Japanese population. The phenotype is compatible with that described in previous reports. Additional supporting evidence concerning progressive hearing loss and deterioration of vestibular function was obtained from our study.
MortonNE. Genetic epidemiology of hearing impairment. Ann N Y Acad Sci. 1991;630:16-31.
2.
RobertsonNGLuLHellerS, et al. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat Genet. 1998;20(3):299-303.
3.
RobertsonNGSkvorakABYinY, et al. Mapping and characterization of a novel cochlear gene in human and in mouse: a positional candidate gene for a deafness disorder, DFNA9. Genomics. 1997;46(3):345-354.
4.
de KokYJBomSJBruntTM, et al. A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects. Hum Mol Genet. 1999;8(2):361-266.
5.
RobertsonNGResendesBLLinJS, et al. Inner ear localization of mRNA and protein products of COCH, mutated in the sensorineural deafness and vestibular disorder, DFNA9. Hum Mol Genet. 2001;10(22):2493-2500.
6.
IkezonoTOmoriAIchinoseSPawankarRWatanabeAYagiT. Identification of the protein product of the COCH gene (hereditary deafness gene) as the major component of bovine inner ear protein. Biochim Biophys Acta. 2001;1535(3):258-265.
7.
UsamiSTakahashiKYugeI, 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(10):744-748.
8.
MiyagawaMNishioSYIkedaTFukushimaKUsamiS. Massively parallel DNA sequencing successfully identifies new causative mutations in deafness genes in patients with cochlear implantation and EAS. PLoS One. 2013;8(10):e75793.
9.
ChangXWangK. wANNOVAR: annotating genetic variants for personal genomes via the web. J Med Genet. 2012;49(7):433-436.
10.
WangKLiMHakonarsonH. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.
11.
AbecasisGRAutonABrooksLD, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56-65.
12.
NaraharaMHigasaKNakamuraS, et al. Large-scale East-Asian eQTL mapping reveals novel candidate genes for LD mapping and the genomic landscape of transcriptional effects of sequence variants. PLoS One. 2014;9(6):e100924.
13.
PollardKSHubiszMJRosenbloomKR, et al. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20(1):110-21.
14.
KumarPHenikoffSNgPC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073-81.
15.
AdzhubeiIASchmidtSPeshkinL, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-9.
16.
ChunSFayJC. Identification of deleterious mutations within three human genomes. Genome Res. 2009;19(9):1553-61.
17.
SchwarzJMRodelspergerCSchuelkeM, et al. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7(8):575-6.
18.
CooperGMStoneEAAsimenosG, et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15(7):901-13.
19.
KempermanMHDe LeenheerEMHuygenPL, et al. Audiometric, vestibular, and genetic aspects of a DFNA9 family with a G88E COCH mutation. Otol Neurotol. 2005;26(5):926-933.
20.
LiepinshETrexlerMKaikkonenA, et al. NMR structure of the LCCL domain and implications for DFNA9 deafness disorder. EMBO J. 2001;20(19):5347-5353.
21.
HildebrandMSGandolfoLShearerAE, et al. A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss. Laryngoscope. 2010;120(12):2489-2493.
22.
BomSJKempermanMHDe KokYJ, et al. Progressive cochleovestibular impairment caused by a point mutation in the COCH gene at DFNA9. Laryngoscope. 1999;109(9):1525-1530.
23.
KhetarpalUSchuknechtHFGacekRRHolmesLB. Autosomal dominant sensorineural hearing loss. Pedigrees, audiologic findings, and temporal bone findings in two kindreds. Arch Otolaryngol Head Neck Surg. 1991;117(9):1032-1042.
24.
KhetarpalU. Autosomal dominant sensorineural hearing loss. Further temporal bone findings. Arch Otolaryngol Head Neck Surg. 1993;119(1):106-108.
25.
MerchantSNLinthicumFHNadolJBJr. Histopathology of the inner ear in DFNA9. Adv Otorhinolaryngol. 2000;56:212-217.
26.
RobertsonNGCremersCWHuygenPL, et al. Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum Mol Genet. 2006;15(7):1071-1085.
27.
NagyIHorvathMTrexlerMRepassyGPatthyL. A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss. J Med Genet. 2004;41(1):e9.
28.
VermeireKBrokxJPWuytsFL, et al. Good speech recognition and quality-of-life scores after cochlear implantation in patients with DFNA9. Otol Neurotol. 2006;27(1):44-49.
29.
StreetVAKallmanJCRobertsonNGKuoSFMortonCCPhillipsJO. A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction. Am J Med Genet A. 2005;139A(2):86-95.
30.
BischoffAMHuygenPLKempermanMH, et al. Vestibular deterioration precedes hearing deterioration in the P51S COCH mutation (DFNA9): an analysis in 74 mutation carriers. Otol Neurotol. 2005;26(5):918-925.
31.
CollinRWPauwRJSchootsJ, et al. Identification of a novel COCH mutation, G87W, causing autosomal dominant hearing impairment (DFNA9). Am J Med Genet A. 2006;140(16):1791-1794.
32.
ChenDYChaiYCYangTWuH. Clinical characterization of a novel COCH mutation G87V in a Chinese DFNA9 family. Int J Pediatr Otorhinolaryngol. 2013;77(10):1711-1715.
33.
DodsonKMGeorgoliosABarrN, et al. Etiology of unilateral hearing loss in a national hereditary deafness repository. Am J Otolaryngol. 2012;33(5):590-594.
34.
KamarinosMMcGillJLynchMDahlH. Identification of a novel COCH mutation, I109N, highlights the similar clinical features observed in DFNA9 families. Hum Mutat. 2001;17(4):351.
35.
PauwRJHuygenPLCollinRW, et al. Phenotype description of a novel DFNA9/COCH mutation, I109T. Ann Otol Rhinol Laryngol. 2007;116(5):349-357.
36.
BaekJIChoHJChoiSJ, et al. The Trp117Arg mutation of the COCH gene causes deafness in Koreans. Clin Genet. 2010;77(4):399-403.
YuanHJHanDYSunQ, et al. Novel mutations in the vWFA2 domain of COCH in two Chinese DFNA9 families. Clin Genet. 2008;73(4):391-394.
39.
ChoHJParkHJTrexlerM, 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(11):1321-1331.
40.
GallantEFranceyLFettingH, et al. Novel COCH mutation in a family with autosomal dominant late onset sensorineural hearing impairment and tinnitus. Am J Otolaryngol. 2013;34(3):230-235.
