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Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.

ABSTRACT: Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood.A total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype.Well-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C?>?T (p.R425X) and one missense mutation c.4994 T?>?C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C?>?T (father and sister) and c.4994 T?>?C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region.Two mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients.

SUBMITTER: Tang F

PROVIDER: S-EPMC5364697 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.

Tang Fengzhu F Ma Dengke D Wang Yulan Y Qiu Yuecai Y Liu Fei F Wang Qingqing Q Lu Qiutian Q Shi Min M Xu Liang L Liu Min M Liang Jianping J

BMC medical genetics 20170323 1

<h4>Background</h4>Many hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic muta ...[more]

PMID: 28335750

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Project description:The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited "absent" or "anomalous" P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

Dataset Information

Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.

Publications

Novel compound heterozygous mutations in the OTOF Gene identified by whole-exome sequencing in auditory neuropathy spectrum disorder.

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