POU4F3 variants are prevalent in Chinese patients with autosomal dominant non-syndromic hearing loss and concurrent tinnitus

POU4F3 (DFNA15) is an established causative gene for autosomal dominant non-syndromic hearing loss (ADNSHL); however, its mutational spectrum in the Chinese population remains incompletely characterized. This study aimed to expand the mutational spectrum of POU4F3 in the Chinese population, to characterize the clinical phenotypes of affected individuals, to describe the proportion of POU4F3 -related families in this referral cohort, and to summarize the global reporting distribution of pathogenic POU4F3 variants in ADNSHL. Among 83 unrelated ADNSHL families evaluated at two tertiary referral centers, nine families harboring POU4F3 variants were identified through whole-exome sequencing and validated by Sanger sequencing with co-segregation analysis. Comprehensive audiological assessments, including pure-tone audiometry, extended high-frequency audiometry, and tinnitus evaluation, were performed on all available family members. Variants were classified according to ACMG/AMP guidelines. Genotype–phenotype correlations were analyzed by integrating data from our cohort with 43 previously published variants. Nine distinct POU4F3 variants were identified, including four novel variants (c.149_152dup, c.687_688delCA, c.704 C > T, and c.709_710delTC) and five previously reported variants (c.371 C > A, c.592 C > A, c.706 C > T, c.952G > A, and EX1-EX2E Del). POU4F3 variants accounted for 10.8% (9/83) of families in this referral cohort, a relatively high proportion compared with those reported in selected European (6.5%), Japanese (2.5%), and Korean (2.4%) cohorts; however, direct comparisons should be interpreted cautiously because of differences in ascertainment, testing strategies, and referral settings. Among 35 confirmed variant carriers, penetrance was complete (100%). Subjective tinnitus was reported by 60.0% (21/35) of affected individuals, with 45.0% (9/20) developing tinnitus prior to measurable hearing loss (lead time range: 0–27 years). Audiometric profiling showed predominantly mid-to-high-frequency sensorineural hearing loss and an age-associated cross-sectional pattern, ranging from milder high-frequency impairment in younger individuals to severe-to-profound broadband loss in older individuals. Exploratory genotype–phenotype analysis suggested that truncating variants may be associated with earlier-onset and more severe hearing loss, whereas missense variants within core DNA-binding domains showed greater phenotypic variability. A compilation of data from the published literature ClinVar identified 82 pathogenic/likely pathogenic POU4F3 variants; 59 (72.0%) were associated with East Asian reports, although this apparent geographic concentration may partly reflect ascertainment and reporting practices. This study identifies four novel POU4F3 variants and shows that POU4F3 variants account for a relatively high proportion of ADNSHL families in this Chinese referral cohort. Consequently, these findings support prioritizing POU4F3 within ADNSHL gene panels, particularly for Chinese and East Asian populations presenting with compatible phenotypes. Furthermore, we propose a literature-informed clinical framework in which the combination of familial ADNSHL, progressive sloping sensorineural hearing loss, and accompanying tinnitus may serve as a practical clinical clue to facilitate early detection, genetic counseling, and timely intervention planning for future gene therapies; prospective validation of this framework is warranted.