Whole exome sequencing identifies TRIOBP pathogenic variants as a cause of post-lingual bilateral moderate-to-severe sensorineural hearing loss.

BACKGROUND

Implementation of whole exome sequencing has provided unique opportunity for a wide screening of causative variants in genetically heterogeneous diseases, including nonsyndromic hearing impairment. TRIOBP in the inner ear is responsible for proper structure and function of stereocilia and is necessary for sound transduction.

METHODS

Whole exome sequencing followed by Sanger sequencing was conducted on patients derived from Polish hearing loss family.

RESULTS

Based on whole exome analysis, we identified two TRIOBP pathogenic variants (c.802_805delCAGG, p.Gln268Leufs610 and c.5014G>T, p.Gly1672, the first of which was novel) causative of nonsyndromic, peri- to postlingual, moderate-to-severe hearing loss in three siblings from a Polish family. Typically, TRIOBP pathogenic variants lead to prelingual, severe-to-profound hearing loss, thus the onset and degree of hearing impairment in our patients represent a distinct phenotypic manifestation caused by TRIOBP variants. The pathogenic variant p.Gln268Leufs610 disrupts the TRIOBP-4 and TRIOBP-5 isoforms (both expressed exclusively in the inner ear and retina) whereas the second pathogenic variant c.514G>T, p.Gly1672 affects only TRIOBP-5.

CONCLUSIONS

The onset and degree of hearing impairment, characteristic for our patients, represent a unique phenotypic manifestation caused by TRIOBP pathogenic variants. Although TRIOBP alterations are not a frequent cause of hearing impairment, this gene should be thoroughly analyzed especially in patients with a postlingual hearing loss. A delayed onset of hearing impairment due to TRIOBP pathogenic variants creates a potential therapeutic window for future targeted therapies.