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Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics.

ABSTRACT: BACKGROUND:While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype-phenotype relationship of this gene as well as efficient molecular testing strategy in the clinic in many populations and to make things more complicated in Koreans, the most prevalent variant p.Arg1939Gln among Korean ANSD children frequently evaded detection by next generation sequencing (NGS), resulting in delayed genetic diagnosis and late cochlear implantation (CI). The aims of this study are to document the mutational and phenotypic spectrum of OTOF-related ANSD (DFNB9) in the Korean population, further establishing genotype-phenotype correlation and proposing a set of the most commonly found OTOF variants to be screened first. METHODS:Genetic diagnosis through the NGS-based sequencing was made on patients with ANSD in two tertiary hospitals. Genotype and phenotypes of eleven DFNB9 patients were reviewed. For data analysis, Mann-Whitney test and Fisher's exact test were applied. RESULTS:This study disclosed four prevalent variants in Koreans: p.Arg1939Gln with an allele frequency of 40.9%, p.Glu841Lys (13.6%), p.Leu1011Pro and p.Arg1856Trp (9.1%). Three novel variants (c.4227?+?5G?>?C, p.Gly1845Glu, and p.Pro1931Thr) were identified. Interestingly, a significant association of p.Arg1939Gln with worse ASSR thresholds was observed despite consistently no ABR response. Ten of 11 DFNB9 patients received CI for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early-CI group (age at CI???18 mo.) than late-CI group. CONCLUSIONS:This study included the largest Korean DFNB9 cohort to date and proposed a set of the most frequent four OTOF variants, allowing the potential prioritization of exons during Sanger sequencing. Further, a significant association of p.Arg1939Gln homozygotes with poor residual hearing was observed. We may have to suspect p.Arg1939Gln homozygosity in cases of poor auditory thresholds in ANSD children with putative negative OTOF variants solely screened by NGS. Reciprocal feedback between bench and clinics regarding DFNB9 would complement each other.

SUBMITTER: Kim BJ

PROVIDER: S-EPMC6260760 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics.

Kim Bong Jik BJ Jang Jeong Hun JH Han Jin Hee JH Park Hye-Rim HR Oh Doo Yi DY Lee Seungmin S Kim Min Young MY Kim Ah Reum AR Lee Chung C Kim Nayoung K D NKD Park Woong-Yang WY Choung Yun-Hoon YH Choi Byung Yoon BY

Journal of translational medicine 20181127 1

<h4>Background</h4>While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype-phenotype relationship of this gene a ...[more]

PMID: 30482216

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Project description: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.

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.

Project description:Auditory neuropathy spectrum disorder (ANSD) is a sensorineural hearing disorder caused by dysfunction of auditory neural conduction. ANSD has a heterogeneous etiology, including genetic factors; the response to cochlear implantation significantly varies depending on the etiology. The results of timely cochlear implantation for OTOF-related ANSD (DFNB9) have been reported to be good. Therefore, identifying the causative gene of ANSD, especially OTOF, is an important issue to rehabilitate these patients.Six sporadic ANSD subjects without anatomical abnormality of the cochlear nerve, including the 4 subjects that were previously reported to be without detectable OTOF mutation, were included. We performed targeted resequencing (TRS) of known deafness genes and multiphasic bioinformatics analyses of the data that ensured detection of capture failure and structural variations. Exclusion of SNP was also double checked. The TRS data previously obtained from 2 subjects were reanalyzed. Through this study, we detected 2 mutant alleles of OTOF from 5 (83.3%) of 6 ANSD subjects. All of the 5 subjects carried at least 1 mutant allele carrying p.R1939Q. This variant was categorized as a simple SNP (rs201326023) in the database and it resided in the exon with frequent capture failures, which previously led to exclusion of this variant from eligible candidacy mistakenly. In addition, we detected a structural variation within OTOF from a previously undiagnosed ANSD subject, which was the second structural variation reported in DFNB9 subjects to date.We identify a strong etiologic homogeneity of prelingual ANSD in case of the anatomically normal cochlear nerve in Koreans and now report DFNB9 as the single overwhelming cause. Multiphasic analysis of TRS data ensuring detection of capture failure and structural variations would be expected to reveal DFNB9 from a substantial portion of previously undiagnosed ANSD subjects in Koreans. Based on our results, we propose a novel strategy that incorporates imaging studies, prevalent mutation screening and multiphasic analysis of TRS data in a stepwise manner to correctly detect DFNB9 in Koreans.

Dataset Information

Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics.

Publications

Mutational and phenotypic spectrum of OTOF-related auditory neuropathy in Koreans: eliciting reciprocal interaction between bench and clinics.

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