Pathogenic mtDNA variants in non-syndromic sensorineural hearing loss: molecular evidence and population diversity

Abstract Background Hearing loss (HL is among the most prevalent inherited sensory disorders, with genetic causes accounting for approximately 50–60% of congenital and early-onset cases. Mitochondrial DNA (mtDNA) variants are increasingly recognized as important contributors to non-syndromic sensorineural hearing loss (NSHL), particularly in maternally inherited and aminoglycoside-sensitive as per established studies. Objective To systematically review mtDNA variants associated with NSHL, evaluate the strength of evidence supporting their pathogenicity, and summarize population-specific prevalence, molecular mechanisms, and clinical implications. Methods A PRISMA-guided literature search was conducted using PubMed, Google Scholar, and manual reference screening for studies published between 2000 and December 25, 2025. Peer-reviewed case reports, family studies, cohort studies, and functional analyses reporting molecularly confirmed mtDNA variants in individuals with isolated NSHL were included. Results Sixty-seven studies met the inclusion criteria. Pathogenic variants were primarily located in the MT-RNR1 and MT-tRNA genes. The m.1555 A > G mutation was the most frequently reported variant, with highest prevalence in East Asian populations. Other recurrent variants included NC_012920.1 m.1494 C > T, m.3243 A > G, m.7444G > A, m.7445 A > G/C, m.7511T > C, and m.7472insC, each demonstrating substantial inter-population variability. Functional studies indicate that these variants impair mitochondrial translation and oxidative phosphorylation, resulting in reduced ATP production and selective vulnerability of cochlear hair cells. Conclusion mtDNA mutations, particularly in MT-RNR1 and MT-tRNA genes, represent significant contributors to NSHL with marked population-specific differences. Incorporation of mtDNA analysis into routine genetic testing, with careful consideration of maternal inheritance and heteroplasmy, is essential for accurate diagnosis, genetic counselling, and prevention of avoidable ototoxicity.