Abstract
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.
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Acknowledgements
This project was supported in part by NIH-NIDCD grant R01′s DC002842, DC012049, and DC017955 (RJHS) and NIH-NIDCD grant 5T32DC000040 (RKT).
Funding
This project was supported in part by NIH-NIDCD grant R01's DC002842, DC012049, and DC017955 (RJHS) and NIH-NIDCD grant 5T32DC000040 (RKT).
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Thorpe, R.K., Azaiez, H., Wu, P. et al. The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study. Hum Genet 141, 853–863 (2022). https://doi.org/10.1007/s00439-021-02340-w
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DOI: https://doi.org/10.1007/s00439-021-02340-w