High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

Abstract EN

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.