Clinical characteristics and influencing factors of children with MT-TL1 gene m.3243 A > G mutation: a phenotypic study based on 11 Han Chinese patients

The m.3243 A > G mutation in the MT-TL1 gene is one of the most common mitochondrial DNA variants, associated with a broad range of clinical phenotypes. While its manifestations in adults have been widely reported, data on pediatric presentations remain limited, particularly in Asian populations. This study aims to characterize the clinical and molecular features of this mutation in a Han Chinese pediatric cohort. We retrospectively analyzed 11 children diagnosed with the m.3243 A > G mutation between 2012 and 2024. Clinical data were collected from medical records and family interviews. Mitochondrial gene testing was performed in patients with suggestive clinical features. Whole-exome sequencing was conducted in selected cases with atypical presentations or negative mtDNA results. The mean age of onset was 5.7 ± 3.2 years, with an average diagnostic delay of 3.35 years. Mutation load ranged from 46.3% to 96.3%. Patients showed marked phenotypic variability despite carrying the same mutation. Neurological (81.8%), gastrointestinal (81.8%), and endocrine (72.8%) symptoms were most common. All patients had elevated lactate levels, and most exhibited muscle weakness or exercise intolerance. MELAS was diagnosed in 63.6% of patients, while 18.2% exhibited NARP-like features and 18.2% were classified as mitochondrial myopathy. One patient developed pancreatitis. No cases of diabetes were observed, although several had a maternal family history. Mutation load in blood did not correlate with clinical severity. This study expands the pediatric phenotypic spectrum of the m.3243 A > G mutation and highlights the complexity of genotype–phenotype correlations. Findings underscore the importance of early suspicion and long-term follow-up in children with unexplained multisystem symptoms, and raise the possibility that nuclear genetic background may contribute to clinical variability, a hypothesis that requires further validation.