AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss.

Autosomal dominant non-syndromic hearing loss (ADNSHL) displays gene-specific progression of hearing loss, which is amenable to sequential audioprofiling. We sought to refine the natural history of ADNSHL by examining audiometric data in 5-year increments. 2175 audiograms were included from four genetic causes of ADNSHL-KCNQ4 (DFNA2), GSDME (DFNA5), WFS1 (DFNA6/14/38), and COCH (DFNA9). Annual threshold deterioration (ATD) was calculated for each gene: for the speech-frequency pure tone average, the ATD, respectively, was 0.72 dB/year, 0.94 dB/year, 0.53 dB/year, and 1.41 dB/year, with the largest drops occurring from ages 45-50 (0.89 dB/year; KCNQ4), 5-10 (1.42 dB/year; GSDME), 40-45 (0.83 dB/year; WFS1), and 50-55 (2.09 dB/year; COCH). 5-year interval analysis of audiograms reveals the gene specific natural history of KCNQ4, GSDME, WFS1 and COCH-related progressive hearing loss. Identifying ages at which hearing loss is most rapid informs clinical care and patient expectations. Natural history data are also essential to define outcomes of clinical trials that test novel therapies designed to correct or ameliorate these genetic forms of hearing loss.