Pathogenic variations in the OTOF gene are a common cause of hearing loss. To refine the natural history and genotype–phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD), audiograms and distortion product otoacoustic emissions (DPOAEs) were collected from a diverse cohort of individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and also reported in the literature. Comparative analysis was undertaken to define genotype–phenotype relationships using a Monte Carlo algorithm. 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency hearing thresholds between missense/missense and LoF/missense genotypes as compared to LoF/LoF genotypes (average hearing threshold for low, middle and high frequencies 70.9, 76.0, and 73.4 dB vs 88.5, 95.6, and 94.7 dB) via Tukey’s test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347, respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes, with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of frequencies measured via DPOAE were lost per year in individuals with serial tests. Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. The unique pattern of variably progressive OTOF-related autosomal recessive ANSD may be amenable to gene therapy in selected clinical scenarios.

OTOF基因的致病性变异是听力损失的常见原因。为了完善与OTOF相关的听神经病谱系障碍 (ANSD)的自然史和基因型-表型相关性，通过综合基因检测从被诊断患有OTOF相关 ANSD的不同人群中收集听力图和失真产物耳声发射 (DPOAE)文献中也有报道。使用蒙特卡洛算法进行比较分析以定义基因型 - 表型关系。来自 49 个 OTOF 阳性个体的 67 个听力图和 25 个DPOAE收集了相关的ANSD。鉴定了 51 种独特的 OTOF 致病变异，其中 21 种是错义的，30 种是功能丧失的（LoF；废话、剪接位点、拷贝数变异和插入缺失）。与 LoF/LoF 基因型相比，错义/错义和 LoF/错义基因型之间的低、中和高频听力阈值存在统计学显着差异（低、中和高频的平均听力阈值分别为 70.9、76.0 和 73.4 dB与 88.5、95.6 和 94.7 dB）通过 Tukey 检验，年龄作为协变量（分别为 P = 0.0180、0.0327 和 0.0347）。青春期听力因错义/错义和 LoF/错义基因型而下降，年中频阈值恶化分别为 0.87 dB/年和 1.87 dB/年。8. 通过 DPOAE 测量的频率在接受连续测试的个体中每年丢失 5%。音频分析OTOF相关的 ANSD 表明 LoF/LoF 基因型的听力明显较差。可变进行性OTOF相关的常染色体隐性遗传 ANSD的独特模式可能适合在选定的临床情况下进行基因治疗。