The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study

Ryan K. Thorpe, Hela Azaiez, Peina Wu, Qiuju Wang, Lei Xu, Pu Dai, Tao Yang, G. Bradley Schaefer, B. Robert Peters, Kenny H. Chan, Krista S. Schatz, Joann Bodurtha, Nathaniel H. Robin, Yoel Hirsch, Zuhair Abdalla Rahbeeni, Huijun Yuan, Richard J.H. Smith

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)853-863
Number of pages11
JournalHuman genetics
Issue number3-4
StatePublished - Apr 2022

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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