Targeted next generation sequencing reveals OTOF mutations in auditory neuropathy spectrum disorder

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Abstract

Objective

To study the genetic etiology of auditory neuropathy spectrum disorder (ANSD) in a Chinese family and perform a literature review of OTOF mutations and cochlear implantation (CI).

Methods

Sequential targeted next generation sequencing (NGS) and CI was performed for the proband. Further, 50 DNA samples from unrelated families with nonsyndromic deafness were examined for frequency determination. The impact of OTOF mutations on hearing recovery after CI was assessed through the literature survey.

Results

In the proband, the targeted NGS panel revealed five suspected variants in four genes (OTOF, EYA4, PCDH15, and GIPC3), of which two mutations—c.5098G > C (p.Glu1700Gln) and c.1702C > T (p.Arg568Trp)—in the OTOF gene were found to be correlated with ANSD. The c.5098G > C allele was identified in only one child from the 50 unrelated participants. The proband's hearing and speech abilities were restored 2 years after the surgery. Most ANSD patients (90.9%; 30/33) with OTOF mutations have acceptable surgical outcomes, as indicated by existing reports.

Conclusions

Our results support the feasibility of CI for patients with ANSD and OTOF mutations, and this hypothesis was supported by the review of existing data. A larger number of cases studies is required to determine possible modifies on the prognosis of surgery.

Introduction

Auditory neuropathy spectrum disorder (ANSD) is a newly documented disease characterized by a non-evoked auditory brainstem response (ABR) and normal response of distortion product otoacoustic emissions (DPOAEs) [1]. The locations of lesions for this condition vary from the spiral ganglions to the ribbon-associated synaptic vesicles in the inner hair cells with preserved function of the outer hair cells, which may also deteriorate eventually [2]. For patients with ANSD who have intact auditory nerves, cochlear implantation (CI) is an effective approach to restore hearing function [1,3].

Various processes and etiologies have been implicated in the pathogenesis of ANSD [1], and genetic testing for several involved genes may help preoperatively identify the location of lesions [4]. The genes identified to be associated with ANSD to date include OTOF, PJVK, LOXHD1, SMAD4, and AIFM1 [[5], [6], [7], [8], [9]]. The OTOF gene spans an approximately 4954 bp transcript and encodes the 1230-amino acid protein otoferlin. In the inner ear, otoferlin is mainly expressed in the hair cells, where it ensures stable exocytosis by the ribbon synapses [7]. OTOF mutations have been reported to be indicators for CI candidates with ANSD in some studies [3,[10], [11], [12], [13], [14], [15], [16], [17], [18]].

In the present study, we used the candidate gene approach with a newly introduced next generation sequencing (NGS) panel covering 154 deafness genes, to examine a Chinese family with ANSD. The existing literature about OTOF mutations and CI was further reviewed through a database search.

Section snippets

Patient recruitment and ethical considerations

The participants included a Chinese family with ANSD and 50 ethnicity-matched unrelated patients with idiopathic hearing impairment. Pathogenic variants in GJB2, SLC26A4, and mitochondrial genes were excluded for all participants by using conventional Sanger sequencing. The proband was a 4.5-year-old girl of Han ethnicity from Dongguan, Guangdong Province. Following an uneventful pregnancy and gestation, a neonatal serum bilirubin test and newborn hearing screening test conducted using

Targeted NGS and mutation verification

The average depth of the targeted region was 487685 bp, and 99.8% of the targeted sequences were included herein. The sequencing depth was 94.16% of the captured bases, with over 30-fold coverage. Five suspected variants in four genes (c.1702C > T/c.5098G > C in OTOF, c.161A > T in EYA4, c.1456G > A in PCDH15, and c.599T > C in GIPC3) with low MAF scores and possible pathogenicity predicted by bioinformatics tools were selected (Table 1). The recessive inheritance and parental verification of

Discussion

In the present study, a targeted NGS panel of deafness genes enabled us to clarify the presence of compound mutations in the OTOF gene. The pathogenicity of c.1702C > T/c.5098G > C was confirmed using parental genetic verification and on the basis of the computational prediction. Identification of the new variant c.1702C > T adds to the current mutation spectrum of OTOF. We performed preliminary studies on another allele, c.5098G > C, in our NSHI cohort but it requires further investigation, as

Conclusions

Our results support the feasibility of CI for patients with ANSD and OTOF mutations, as indicated by the findings of and the literature review in this study. A larger number of case studies are required to determine the possible prognoses of surgery.

Conflicts of interest

None.

Acknowledgements

We thank all participants in this study for their cooperation. The study was supported by grants from the National Natural Science Foundation of China (No. 81500802, 81700912) and the Natural Science Fund of Guangdong Province (No. 2015A030310072, 2016A030310286).

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