# Identification of alternative splicing in WFS1 associated with low-frequency hearing loss in the common marmoset

## TL;DR

The study identifies alternative splicing in the WFS1 gene linked to low-frequency hearing loss in marmosets, offering insights for genetic diagnosis and therapies.

## Contribution

The study uses common marmoset RNA-seq data to reveal alternative splicing in WFS1 associated with low-frequency hearing loss.

## Key findings

- Alternative splicing patterns in WFS1 correlate with low-frequency hearing loss in marmosets.
- Marmoset cochlear RNA-seq data provides a better model for understanding human hearing loss mechanisms.
- WFS1 variants show distinct expression patterns across cochlear turns.

## Abstract

Approximately 200 genes have been identified as causative in hereditary hearing loss. Genetic testing is increasingly important, not only for accurate diagnosis but also for predicting audiometric profiles, prognoses, and potential syndromic features. Hereditary hearing loss can be syndromic or nonsyndromic, with nonsyndromic forms further classified by inheritance: autosomal-dominant or autosomal-recessive. In autosomal-dominant cases, three pathological mechanisms—haploinsufficiency, dominant-negative effects, and gain of function—are often implicated. Moreover, specific genes correlate with distinct audiometric patterns: WFS1 variants typically cause low-frequency hearing loss, whereas KCNQ4 and POU4F3 variants are linked to high-frequency loss. To investigate the underlying mechanisms of these frequency-dependent patterns, gene expression across cochlear turns was compared in mice, but interpretations of the results were limited because of inherent structural differences between rodent and primate cochleae. Therefore, the common marmoset (Callithrix jacchus), which offers closer anatomical and functional similarity to human cochleae, was utilized herein as an improved model. Using RNA sequencing (RNA-seq) across cochlear turns of common marmosets, the present study aimed to uncover gene expression and alternative splicing patterns that may explain tonotopic manifestations in hereditary hearing loss, including those caused by WFS1 variants, the present study being one such using common marmoset cochlear RNA-seq data, and these findings are highly valuable for genetic diagnosis and the development of gene therapies.

Frequency-specific hearing loss in autosomal-dominant deafness is linked to distinct genes, such as WFS1 for low-frequency loss. RNA sequencing of cochlear turns in the common marmoset reveals alternative WFS1 splicing patterns that may underlie tonotopic vulnerability.