KCNQ4 c.546C>G variant is associated with early-onset high-frequency hearing loss, tinnitus, and cardiovascular comorbidities in Taiwanese adults

KCNQ4 encodes a voltage-gated potassium channel essential for ion balance and membrane potential regulation in inner ear hair cells. Mutations in KCNQ4 are associated with late-onset, high-frequency hearing loss that progressively worsens. This study aimed to compare carriers of the KCNQ4 c.546C>G variant with non-carriers to examine the relationship between this mutation and hearing loss, tinnitus, and cardiovascular diseases. This case-control study used data from the Taiwan Precision Medicine Initiative (TPMI) at Taichung Veterans General Hospital. A total of 95 KCNQ4 c.546C>G carriers and 95 non-carriers were recalled between August 2022 and June 2023. Participants underwent pure-tone audiometry, completed the Tinnitus Handicap Inventory (THI), and provided medical histories. Chi-square and Fisher's exact tests were used to compare categorical variables, and logistic regression assessed associations between various factors, THI scores, and hearing loss. The KCNQ4 carrier group showed significant hearing loss at 4 kHz (21.3 ± 16.1 dB) and 8 kHz (26.4 ± 21.6 dB), with greater severity at higher frequencies. The proportion of hearing loss was highest at 8 kHz (49.5%), followed by 4 kHz (33.7%) and 2 kHz (21.1%). THI scores and incidence of cardiovascular diseases were also significantly higher among carriers. Factors affecting mid- and high-frequency hearing loss included the KCNQ4 variant (odds ratio [OR], 2.07) and age (OR, 1.12). After adjusting for cardiovascular disease, carriers still exhibited significant hearing loss at 4 kHz and 8 kHz. Carriers younger than 40 years had a higher risk of hearing loss at 8 kHz (OR, 4.89). Genetic testing for the KCNQ4 c.546C>G variant and annual audiometric evaluations are strongly recommended for patients under 40 years old with high-frequency hearing loss, tinnitus, and cardiovascular comorbidities.