An ultra-rare missense variant in the KIF1B gene linked to autoinflammatory Menière's disease.

Abstract

Menière's disease (MD) is an inner ear disorder characterised by episodes of vertigo, sensorineural hearing loss and tinnitus linked to autoinflammation and/or type 2 immune response. We hypothesise that rare variation in immune response genes could drive the autoinflammatory phenotype in MD. We retrieved differentially expressed genes (DEG) from single-cell RNAseq and epigenomic datasets to search for rare variants in the MD exome (N = 454) and genome (N = 511) sequencing datasets. The variant chr1:10374335 C > T in the KIF1B gene was found in three MD unrelated individuals and was predicted to be likely pathogenic. According to differential transcript usage, transcript ENST00000622724.3 was found in MD samples, but absent in controls. Furthermore, this variant may influence splicing through the generation of exonic enhancers and silencers, potentially changing transcription factor binding at the promoter. These findings support that this KIF1B gene rare variant is associated with the MD autoinflammatory phenotype and may up-regulate its expression in monocytes.