Abstract
To decipher the genotype-phenotype correlation of auditory neuropathy (AN) caused by AIFM1 variations, as well as the phenotype progression of these patients, exploring the potential molecular pathogenic mechanism of AN. A total of 36 families of individuals with AN (50 cases) with AIFM1 variations were recruited and identified by Sanger sequencing or next-generation sequencing; the participants included 30 patients from 16 reported families and 20 new cases. We found that AIFM1-positive cases accounted for 18.6% of late-onset AN cases. Of the 50 AN patients with AIFM1 variants, 45 were male and 5 were female. The hotspot variation of this gene was p.Leu344Phe, accounting for 36.1%. A total of 19 AIFM1 variants were reported in this study, including 7 novel ones. A follow-up study was performed on 30 previously reported AIFM1-positive subjects, 16 follow-up cases (53.3%) were included in this study, and follow-up periods were recorded from 1 to 23 years with average 9.75 ± 9.89 years. There was no hearing threshold increase during the short-term follow-up period (1-10 years), but the low-frequency and high-frequency hearing thresholds showed a significant increase with the prolongation of follow-up time. The speech discrimination score progressed gradually and significantly along with the course of the disease and showed a more serious decline, which was disproportionately worse than the pure tone threshold. In addition to the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is also observed in AIFM1-related AN and affects females. In conclusion, we confirmed that AIFM1 is the primary related gene among late-onset AN cases, and the most common recurrent variant is p.Leu344Phe. Except for the X-linked recessive inheritance pattern, the X-linked dominant inheritance pattern is another probability of AIFM1-related AN, with females affected. Phenotypical features of AIFM1-related AN suggested that auditory dyssynchrony progressively worsened over time.
Highlights
Auditory neuropathy (AN) is a special type of sensorineural hearing loss with a main manifestation of impaired speech comprehension, accounting for 1.2-10% of cases of hearing loss, depending on the population [1, 2]
There is no frequency data of AIFM1-positive cases in AN cases. We further identified another 20 AN cases with AIFM1 variants, including 7 novel variants and one hotspot variant, showing that the proportion of AN caused by AIFM1 in Chinese patients with delayed-onset AN was as high as 18.6% (36/194), higher than the 15.53% (16/103) observed in the previous study [6]
HCs and spiral ganglion neuron (SGN) are very important for hearing ability; HCs convert the sound waves into electrical signals, and SGN transmit the electrical signals into the auditory cortex for hearing ability [29]
Summary
Auditory neuropathy (AN) is a special type of sensorineural hearing loss with a main manifestation of impaired speech comprehension, accounting for 1.2-10% of cases of hearing loss, depending on the population [1, 2]. The affected hearing in AN is mainly low frequency, and the speech recognition rate is obviously disproportionately lower than the pure tone threshold (PTA). This type of disease may arise from the inner hair cells (IHCs) of the cochlea, the synapses between the IHCs and the auditory nerve, the spiral ganglion neuron (SGN), the cochlear nerve fibers, and one or more of the auditory nerves [3].
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