# Frequency and Hearing Loss Phenotypes of OPA1 Variants in a Cohort of 18,475 Patients with Hearing Impairment

## TL;DR

This study finds that OPA1 gene variants are a rare but significant cause of hearing loss, often linked to auditory neuropathy and optic atrophy.

## Contribution

The study identifies OPA1 as a rare cause of hearing loss and explores genotype-phenotype correlations in a large patient cohort.

## Key findings

- Ten individuals with OPA1 variants were identified in 18,475 patients with hearing loss.
- OPA1-related hearing loss is typically post-lingual, progressive, and associated with auditory neuropathy spectrum disorder.
- Cochlear implants provided better outcomes than hearing aids for some patients with OPA1-related hearing loss.

## Abstract

Background/Objectives: The OPA1 gene encodes a dynamin-related GTPase essential for mitochondrial fusion. Variants in OPA1 are a major cause of autosomal dominant optic atrophy (DOA). A subset of DOA patients exhibits hearing loss, often manifesting as auditory neuropathy spectrum disorder (ANSD). In this study, we aimed to describe the frequency of OPA1-related hearing loss in a large cohort of patients with hearing loss and to explore the genotype–phenotype correlations and appropriate interventions. Methods: A total of 18,475 Japanese patients with hearing loss were recruited. Targeted massively parallel sequencing of 158 deafness-related genes was performed, and individuals with OPA1 variants were identified. Clinical data, including age of onset, audiological findings, and systemic features, were retrospectively reviewed. Results: Ten individuals from eight independent families carrying OPA1 variants were identified. Three variants were classified as pathogenic or likely pathogenic, while five were variants of uncertain significance. Hearing loss was typically post-lingual in onset and progressive, with predominantly mild-to-moderate severity. Missense variants tended to be associated with DOA-plus phenotypes and ANSD. Five patients obtained only limited benefit from hearing aids, whereas one patient who received a cochlear implant achieved good speech perception. Conclusions: OPA1 is a rare causative gene for hearing loss and is frequently associated with the ANSD phenotype. Affected individuals exhibited phenotypic heterogeneity, which may reflect incomplete penetrance or the influence of mitochondrial DNA-related factors.