Abstract: Purpose: Heterozygous variants of the KCNQ4 gene are associated with isolated sensorineural hearing loss (DFNA2A). This study aimed to determine the frequency and clinical characteristics of pathogenic, likely pathogenic, and uncertain variants in the KCNQ4 gene among patients with sensorineural hearing loss of unknown origin in North Spain. Methods: We conducted a prospective observational study of patients with sensorineural hearing loss of unknown etiology at a tertiary hospital over six years. Next-generation sequencing carried out with a panel of genes was used to identify genetic variants related to both syndromic and non-syndromic hearing loss. Results: Among 370 patients, seven (1.89%) harbored pathogenic or likely pathogenic variants in the KCNQ4 gene: c.777_778delinsCC, c.626 T > G, and c.778G > C. None of these variants had been previously described. One patient also had a variant of uncertain significance (c.419 T > C). All patients exhibited progressive bilateral sensorineural hearing loss, predominantly at high frequencies, with variable onset and severity. None reported dizziness or vertigo. Five patients used hearing aids, and one received a cochlear implant with good results. Conclusions: KCNQ4 gene variants are rare in Cantabria, present in less than 2% of patients with sensorineural hearing loss of unknown origin. Although most variants identified in our study had not been previously described, the observed phenotype aligned with the typical presentation: bilateral, progressive sensorineural hearing loss with variable onset and severity. Some patients may benefit from cochlear implants.

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