Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Human genetics, 2022-04, Vol.141 (3-4), p.853-863

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2022

Link zum Volltext

Quelle

SpringerLink

Beschreibungen/Notizen

• 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.