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

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.

Figure 1:

Map of causative OTOF variants included in this study, based on transcript NM_001287489.2. A, Illustration of splice site variants and CNVs. B, Illustration of coding variants; variants in red are deletions and/or insertions, variants in green are nonsense mutations, and variants in purple are missense mutations. CNV = copy number variant. † = this CNV is a deletion with breakpoints of chromosome 2:26695190–26700779.

Figure 2:

Audioprofile generated by taking the average hearing level (HL) of all 67 patients with OTOF-related hearing loss included in this study. Error bars are the standard deviations.

Figure 3:

Stratified audioprofiles of individuals with OTOF-related hearing loss included in this study. A, audioprofiles based on OTOF genotype (MM, LM, and LL). B, audioprofiles based on individuals with an MM genotype, grouped into age bins. C, audioprofiles based on individuals with an LM genotype, grouped into age bins. D, audioprofiles based on individuals with an LL genotype, grouped into age bins. HL = hearing level, MM = missense/missense, LM = loss of function/missense, LL = loss of function/loss of function.

Figure 4:

DPOAE results from four individuals with OTOF-related hearing loss with sequential tests. Each individual had two ears tested at each time point; ears from the same individual are represented using the same shape on each graph point. Genotype is listed for each individual. DPOAE results are reported as proportion of frequencies that were present and normal compared with all frequencies tested.