Auditory Neuropathy Caused by a Structural Variation in the OTOF Gene, Identified Using Oxford Nanopore Adaptive Sampling

TL;DR

Researchers identified a new genetic duplication in the OTOF gene causing auditory neuropathy using advanced sequencing techniques.

Contribution

First report of a large duplication variant in the OTOF gene causing auditory neuropathy, confirmed using Oxford Nanopore adaptive sampling.

Findings

A four-year-old male with auditory neuropathy had a 5254-base duplication in the OTOF gene.

The duplication included exons 14 to 18 of the OTOF gene NM_001287489.

Oxford Nanopore adaptive sampling confirmed the trans configuration of the duplication and a single nucleotide variant.

Abstract

Background/Objectives: The OTOF gene is reported to be the causative gene for non-syndromic recessive sensorineural hearing loss and auditory neuropathy spectrum disorder. About 300 variants have been reported, but there have been no reports to date on copy gain variants. Methods: We identified a copy gain variant in the OTOF gene through short-read next-generation sequencing analysis from one patient with auditory neuropathy. We also performed long-read next-generation sequencing analysis using the Oxford Nanopore Technologies adaptive sampling procedure. Results: The four-year-old male carried a duplication of chr2: 26,477,852 to 26,483,106 (a 5254-base duplication including exon 14 to exon 18 of the OTOF gene NM_001287489) and a c.5385C>A single nucleotide variant. We also confirmed that these two variants were located in the trans configuration based on haplotype phasing results using the long-read next-generation sequencing data. Conclusions: This is the first report of an auditory neuropathy patient with a large duplication variant in the OTOF gene. The identified variants were novel, but based on the clinical phenotype of the patient, these variants seem to be the genetic cause of this patient’s phenotype. Oxford Nanopore Technologies adaptive sampling is a powerful tool for the analysis of structural variants (particularly for determining the breakpoint and direction) and haplotype phasing.

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