Unraveling the genetic basis of post-infancy diagnosed sensorineural hearing loss using whole exome sequencing

To clarify the genetic causes and the mutation spectrum of post-infancy diagnosed sensorineural hearing loss in the Chinese population.

We enrolled patients with post-infancy diagnosed bilateral sensorineural hearing loss (onset age between 1 and 60 years) at the Eye & ENT Hospital of Fudan University from November 2018 to October 2022. Whole-exome-sequencing (WES) was performed to elucidate the genetic etiology of these patients. Additionally, the frequency of common deafness variants was retrospectively analyzed and compared to previous studies.

In this study, 146 patients with post-infancy diagnosed sensorineural hearing loss received WES, of which 93 patients had a positive molecular diagnosis, with an overall diagnostic rate of 63.7 %. A total of 107 variants across 50 deafness-related genes were identified. Among the diagnosed patients, GJB2: c.109G>A (11.6 %), GJB2: c.235delC (7.2 %), SLC26A4: c.919-2A>G (5.1 %), MPZL2: c.220C>T (2.4 %), and SLC26A4: c.2168A>G (2.1 %) were the five variants with the highest frequency. The diagnostic rate in the patients with inner ear malformations (100 % vs 59.5 %, P < 0.05) and patients with onset before age of 18 years (68.9 % vs 48.7 %, P < 0.05) was significantly higher than in patients without inner ear malformations and with an onset after age of 18 years.

This study has preliminarily outlined the spectrum of gene mutations associated with deafness in patients with post-infancy diagnosed hearing loss within the Chinese population. We identified 15 novel pathogenic or likely pathogenic variants, indicating that the GJB2 c.109G>A is the most common variant in post-infancy diagnosed hearing loss patients, and the proportion of patients with MPZL2 variants is higher than expected. Our study provides valid evidence to support subsequent genetic testing for patients with post-infancy diagnosed hearing loss.