The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
30
04
2021
accepted:
07
08
2021
pubmed:
24
8
2021
medline:
27
4
2022
entrez:
23
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34424407
doi: 10.1007/s00439-021-02340-w
pii: 10.1007/s00439-021-02340-w
pmc: PMC9093589
mid: NIHMS1804191
doi:
Substances chimiques
Membrane Proteins
0
OTOF protein, human
0
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
853-863Subventions
Organisme : NIDCD NIH HHS
ID : 5T32DC000040
Pays : United States
Organisme : NIDCD NIH HHS
ID : T32 DC000040
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC012049
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC002842
Pays : United States
Organisme : NIDCD NIH HHS
ID : DC002842
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC017955
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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