Identification of a novel POU4F3 frameshift variant in a Chinese family with autosomal dominant hearing loss

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is characterised by highly clinical and genetic heterogeneity. A variant of POU4F3 is considered the pathogenic cause of ADNSHL, specifically designated as autosomal dominant nonsyndromic deafness 15 (DFNA15). The aim of this study was to explore the genetic variants and molecular pathogenic mechanism for a Chinese pedigree with DFNA15. A Chinese family with deafness underwent physical and otoscopic examinations, hearing measurements, and whole-exome sequencing. Sanger sequencing and segregation analysis were used to confirm the variants in the patients and healthy controls. The pathogenicity of the variants was detected using molecular modelling, immunoblotting and immunofluorescence experiments. The patients showed bilateral, late-onset, progressive and sensorineural hearing loss without any other systemic diseases. Whole-exome and Sanger sequencing revealed a novel pathogenic variant, c.288dup, within the POU4F3 gene in the large Chinese family, which entirely cosegregated with the disease phenotype. The variant produced a truncated protein without functional domains, as determined using modelling, and theoretically destroyed the function of POU4F3. Immunofluorescence experiments revealed that the subcellular localisation of the mutant protein differed from that of wild-type protein, which could damage its normal function. In addition, immunoblotting experiments indicated that the mutant had lower protein expression than the wild type. We first identified the frameshift variant (c.288dup, p.Ile97Hisfs*75) of POU4F3 associated with DFNA15. This study enriches the mutation spectrum of POU4F3 associated with hearing impairment and would help to illustrate the molecular pathogenic mechanism of POU4F3.