[Origin of mitochondrial A1555G heterogeneous mutation and its correlation with hearing loss severity]

Objective: To explore the genesis of the mitochondrial A1555G mutation and its correlation with the severity of hearing impairment. Methods: A cross-sectional study was conducted. Individuals with the mitochondrial A1555G mutation who were screened for neonatal deafness genes at the Molecular Diagnostic Center for Deafness, PLA General Hospital, between January 2020 and December 2023 were selected to analyze the proportions of heterogeneous and homogeneous variants. Meanwhile, individuals with the mitochondrial A1555G heterogeneous mutation identified through next-generation sequencing in the outpatient database of the Department of Otolaryngology, Head and Neck Surgery, PLA General Hospital from January 2016 to December 2023 were selected for analysis of their genetic origins and phenotypic characteristics. The correlation between the severity of hearing loss and the A1555G mutation load was further explored by examining individuals with known mutation load and their corresponding hearing phenotypes. Results: Among the 65 942 newborns, 157 individuals (63 males and 94 females) were found to carry the A1555G mutation (2.4 per thousand individuals) (157/65 942). There were 48 individuals carrying heterogeneous mutation (7 per ten thousand individuals) (48/65 942), and 30.6% (48/157) of the individuals carrying A1555G mutation had heterogeneous mutation. Among the A1555G heteroplasmy individuals, there were five cases of neonatal mutation, 14 cases of clear mutation load, and the mutation load ranged from 1.0% to 99.4%. Two cases showed bilateral extremely severe hearing loss, and one case exhibited unilateral extremely severe hearing loss. Analysis of 118 cases involving the A1555G mutation load and hearing phenotype, including heteroplasmy individuals, revealed a positive correlation between the degree of hearing loss and the mutation load (r=0.489, 95%CI: 0.350-0.606, P<0.001). Additionally, the mutation load in individuals with moderate to severe hearing loss was greater than 50% in all cases (52/52). Conclusions: The current study indicates that some of the genetic sources of A1555G heterogenous mutation individuals are de novo mutations. There is a wide variation range in the mutation load among individuals carrying the A1555G variant, and a positive correlation exists between the mutation load and the severity of hearing loss, particularly in cases of moderate to severe hearing impairment.