No Association Between Autism Spectrum Disorder and Mitochondrial DNA Variants: A Comprehensive Genetic Study in...

Autism spectrum disorder (ASD) has a strong genetic basis, yet specific etiological factors remain unidentified in the majority of cases. Mitochondrial DNA (mtDNA) variations have been hypothesized as potential contributors to ASD development. However, the precise role of mtDNA remains unclear due to inconsistent findings across studies, which often suffer from methodological limitations.

This study aimed to comprehensively investigate the association between mtDNA variants, gene-level variant burden and haplogroup distributions in a Turkish paediatric ASD cohort.

Case control study.

Whole mtDNA analysis of peripheral blood samples from 95 children with ASD and 95 healthy controls was performed using next-generation sequencing. Identified variations were evaluated for pathogenicity via genomic databases and in silico analyses. Potentially pathogenic variations underwent segregation analysis. Additionally, mtDNA haplogroup distributions were compared between the groups.

The overall frequency of mtDNA variants was significantly higher in the ASD group than in the control group (p = 0.033). The ASD cohort harboured 23 distinct variants (initially classified as three pathogenic/likely pathogenic (P/LP) and 20 variants of uncertain significance [VUS]); while the control group had 13 VUS and no P/LP variants. Gene-based burden analysis identified a significantly higher variant load in the MT-CYB gene within the ASD cohort (FDR = 0.048). However, segregation analysis of the P/LP variants (including m.827A > C, m.9804G > A and a novel MT-CYB variant) revealed maternal inheritance from asymptomatic mothers. Consequently, all P/LP variants were reclassified as VUS. No significant difference was found in mtDNA haplogroup distribution between groups.

Through comprehensive mtDNA scanning and rigorous pathogenicity assessment, our findings suggest that mtDNA variations are not implicated in the pathogenesis of ASD. However, given the complex nature of ASD, future research is needed with larger sample sizes, standardized pathogenicity assessment criteria and detailed phenotypic analyses to further elucidate the relationship between mtDNA variants and ASD.