Analysis Of Genotype And Audiological Characteristics In Patients With OTOF Gene Mutations Related Auditory Neuropathy

Objective To explore the genotype profiles,phenotype profiles,progress of disease,intervention,correlation between genotype and phenotype of patients with OTOF gene mutations related auditory neuropathy(AN).Methods This study was based on the multicenter study on the diagnosis and treatment of AN in China(ChiCTR2100050125).Diagnosis of AN according to Chinese clinical practice guideline of auditory neuropathy.Using whole-exome/Panel sequencing techniques and American college of medical genetics and genomics(ACMG)guidelines for interpreting disease variants to analyze and screen AN patients associated with OTOF gene mutations.Conduct audiometric tests,including auditory brainstem response(ABR),distortion product otoacoustic emission(DPOAE),behavioral audiometry/pure tone audiometry,etc.The genetic characteristics and audiological characteristics of the patients were analyzed.The disease progression and intervention of the patients were followed up,and phenotype differences were analyzed in combination with genotype.Results 1.Forty-three AN patients identified OTOF gene mutation as the cause of disease.The ratio of male to female was 1.15:1,the testing age was 0.33～28(3.35±5.45)years old,and the age of onset was 0～3(1.02±0.75)years old.2.ABR was absent or severely abnormal,and cochlear microphonic(CM)can be recorded.Electrocochleogram(ECochG)showed that the amplitude ratio of summating potential(SP)and action potential(AP)was greater than 0.4,and most(66.67%)-SP/AP amplitude ratio was greater than 1.The average extraction rate of DPOAE was 68.15%.The grade of hearing loss ranges from moderate to total deafness,with 91.11%of severe and above hearing loss.The pure-tone average(PTA)was 89.20 ± 17.81 dB HL.3.Thirty-two of 43 patients were followed up for 0.25～12.17(3.31±3.78)years.Each frequency threshold of multifrequency steady-state auditory evoked potential(ASSR)has decreased,and the annual decrease threshold is 9.56,1.99,4.30 and 14.10 dB respectively.The DPOAE extraction rate decreased from 62.50%to 50.00%,and the annual deterioration rate was 17.35%.Twenty-five patients underwent cochlear implantation(CI).The age of initial implantation was 3.00(2.00,4.00)years,the duration of intervention was 3.50(2.25,6.00)years,Category of Auditory Performance(CAP)was 7.00(5.00,7.50),and Speech intelligibility rating(SIR)was 4.00(3.00,4.50).4.Fifteen OTOF gene variants were newly discovered.Compared to patients with loss of function(Lof)mutation in single alleles and those with non-Lof mutations in both alleles,patients with Lof mutation in both alleles have a trend of worse hearing threshold and better DPOAE extraction rate..The DPOAE extraction rate of patients with protein truncation caused by single allele variation is better than that of patients with protein truncation caused by dual allele variation,and there is no difference in hearing threshold.Conclusion 1.With the increase of the course of disease,the disease shows progression in ASSR and DPOAE tests.The CI effect of AN patients associated with OTOF gene mutations is good,and it is related to the intervention age and intervention duration.2.There is a correlation trend between genotype and phenotype.Compared with the missense mutation,the Lof mutation has a tendency to be associated with slightly severe hearing loss and slightly better DPOAE elicitation phenotype.The variation that leads to protein truncation has a tendency to be associated with slightly severe hearing loss and slightly better DPOAE elicitation.