Journal article
The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study
Human genetics, Vol.141(3-4), pp.853-863
04/2022
DOI: 10.1007/s00439-021-02340-w
PMCID: PMC9093589
PMID: 34424407
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.
Details
- Title: Subtitle
- The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study
- Creators
- Ryan K Thorpe - Roy J. and Lucille A. Carver College of MedicineHela Azaiez - University of IowaPeina Wu - Chinese Academy of Medical Sciences & Peking Union Medical CollegeQiuju Wang - Chinese PLA General HospitalLei Xu - Shandong UniversityPu Dai - Chinese PLA General HospitalTao Yang - Shanghai Jiao Tong UniversityG Bradley Schaefer - University of Arkansas for Medical SciencesB Robert Peters - Dallas Ear InstituteKenny H Chan - Boston Children's HospitalKrista S Schatz - Johns Hopkins UniversityJoann Bodurtha - Johns Hopkins UniversityNathaniel H Robin - University of Alabama at BirminghamYoel Hirsch - Dor Yeshorim, The Committee of Preventing Jewish Genetic Diseases, Brooklyn, NY, USA.Zuhair Abdalla Rahbeeni - Medical Genetics Department, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.Huijun Yuan - Medical Genetics CenterRichard J H Smith - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Human genetics, Vol.141(3-4), pp.853-863
- DOI
- 10.1007/s00439-021-02340-w
- PMID
- 34424407
- PMCID
- PMC9093589
- NLM abbreviation
- Hum Genet
- ISSN
- 0340-6717
- eISSN
- 1432-1203
- Grant note
- DC002842 / NIDCD NIH HHS R01 DC012049 / NIDCD NIH HHS R01 DC017955 / NIDCD NIH HHS 5T32DC000040 / NIDCD NIH HHS
- Language
- English
- Date published
- 04/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256927902771
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