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

Abstract

BackgroundWhile 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.MethodsGenetic 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.ResultsThis 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.ConclusionsThis 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.

Flexible Real-Time Polymerase Chain Reaction-Based Platforms for Detecting Deafness Mutations in Koreans: A Proposed Guideline for the Etiologic Diagnosis of Auditory Neuropathy Spectrum Disorder

“…In detail, OTOF variants (p.Glu841Lys, p.Arg1856Trp, p.Leu1011Pro, p.Tyr1064Ter, and p.Arg1939Gln) were highly prevalent among Korean and East Asian prelingual ANSD ( Supplementary Table S1). OTOF variants, including a founder variant (p.Arg1939Gln) among Koreans, account for approximately 90% of Korean prelingual ANSD cases with anatomically intact cochlear nerves [14]. Consistent with this, OTOF p.Arg1939Gln was found in 20 of the 26 alleles (76.9%) among Japanese congenital or early-onset ANSD cases and the founder effect was determined for this variant [21].…”

“…Recent studies have shown a higher genetic load of OTOF variants explaining 91% of prelingual ANSD in Koreans with an anatomically intact cochlear nerve [14]. Furthermore, understanding the distribution pattern of the Korean OTOF alleles, which are predominantly concentrated on certain exons among Korean prelingual ANSD, could provide a justification for proposing a set of the most frequent OTOF variants to be included in the first-line screening [14,15]. As a result, the new genotyping kit developed in this study exclusively comprises the five most prevalent missense variants of OTOF causing prelingual ANSD in the Korean population, showing perfect agreement with Sanger sequencing analysis.…”

“…As a result, the new genotyping kit developed in this study exclusively comprises the five most prevalent missense variants of OTOF causing prelingual ANSD in the Korean population, showing perfect agreement with Sanger sequencing analysis. Recently, the authors disclosed that the NGS-based targeted resequencing of the known 134 deafness genes does not necessarily guarantee the accurate detection of causative variants, particularly, the major allele (p.Arg1939Gln) of Korean ANSD with prelingual onset, due to capture failures and poor coverage of the last exon of the cochlear isoforms of OTOF [14,15]. Furthermore, Sanger sequencing of OTOF is often hindered by the large size of this gene, which comprises 46 exons, and additionally, not all clinics are equipped with a sequencer for Sanger sequencing [26].…”

“…For example, we recently found that four prevalent OTOF variants account for about 70% of Korean prelingual auditory neuropathy spectrum disorder (ANSD) with the anatomically intact cochlear nerve [14], making it unnecessary to go through other deafness genes irrelevant to such a phenotype. Furthermore, the predominant variant, p.Arg1939Gln, of OTOF, was frequently missed during NGS-based targeted exome sequencing due to capture failures and the poor coverage of the last exon of the cochlear isoforms of OTOF [14,15]. Considering this, a genotyping kit that facilitates screening exclusively for such prevalent OTOF variants would minimize the time and cost of NGS in Korean prelingual ANSD.…”

Genetic Information and Precision Medicine in Hearing Loss

“…Without this genetic information, HL in patients with CAPOS syndrome would be considered "central" due to the accompanying deficits of the central nervous system, precluding the implementation of CI in these subjects. OTOF-related prelingual ANSD patients are also considered to have good prognosis for CI, if CI can be performed in a very timely fashion [15]. Considering the amount of residual hearing, it would be highly unlikely to perform early CI in those patients without the genetic information.…”