Ó³»­´«Ã½

BACKGROUND: Understanding the phenotypic spectrum of disease-associated genes is essential for accurate diagnosis and targeted therapy. (FERM and PDZ Domain Containing 4) has previously been associated with intellectual disability and epilepsy. However, its potential role in non-syndromic hearing loss has not been explored.METHODS: We performed genetic analysis in two unrelated families presenting with non-syndromic sensorineural hearing loss, identifying maternally inherited missense variants in . Clinical phenotyping included audiological assessment and evaluation for neurodevelopmental involvement. Cross-species expression analyses were conducted in , zebrafish, and mouse. Functional characterization included quantitative evaluation of sound-evoked responses in () mutants, assessment of neuronal development and acoustic startle responses in zebrafish loss of function models, and morphological cochlear analyses with auditory brainstem response measurements in knockout mice.RESULTS: Three affected males from two unrelated families presented with prelingual, bilaterally symmetrical sensorineural hearing loss, with confirmed congenital onset in one individual and no evidence of neurodevelopmental abnormalities. Cross-species analyses demonstrated evolutionarily conserved expression of in auditory structures. In , quantitative analysis of sound-evoked responses in mutants revealed impaired auditory function. Zebrafish loss of function models exhibited reduced neuronal populations in the otic vesicle and posterior lateral line, abnormal neuromast development, and diminished acoustic startle responses. In mice, knockout resulted in high-frequency hearing loss and cochlear abnormalities consistent with the human phenotype.CONCLUSIONS: Our findings expand the phenotypic spectrum of to include non-syndromic sensorineural hearing loss and establish its evolutionarily conserved role in auditory function. These results have direct implications for genetic diagnosis and variant interpretation in patients with hearing loss.