Sex differences in the genetics of autism spectrum disorder and their impact on gene expression associated with mitochondrial function

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects social-communicative skills and is characterized by restricted and stereotyped behaviors. It affects more males, with a ratio of 4:1, and has a prevalence of 1:54 children. Manifestations of ASD vary by gender, with specific behaviors less pronounced in females. Using data from the Gene Expression Omnibus repository, this research explored sex-related genetic differences in ASD and their impact on mitochondrial gene expression. Peripheral blood DNA was found to exhibit differential methylation patterns by sex, with additional alterations in individuals with ASD. Sex-specific transcriptional changes were also identified in cord blood from high-risk ASD pregnancies. Of 50 genes with differential methylation by sex, only the PLEKHN1 gene is related to mitochondrial function. Age correlated with symptoms and diagnosis in males, whereas PLEKHN1 methylation was associated with age and internalizing symptoms in females. In conclusion, sex influences genetic contributions in ASD, affecting mitochondrial gene expression. • Data from three GEO datasets (GSE123302, GSE109905, GSE164563) were used to evaluate sex differences in genetic contributions to ASD and their implications on mitochondrial gene expression. • Sex-Dependent Methylation : Significant changes in DNA methylation in ASD patients versus non-autistic individuals. o Key Genes : LYRM4 , ACSM3 , DNAJA1 , and ABCB8 , all linked to mitochondrial functions. • Transcriptional Analysis : Significant sex differences in gene expression in umbilical cord blood from high-risk ASD pregnancies. o Key Genes : CA5B and CA5BP1 , related to mitochondrial functions. • Epigenetic Differences : PLEKHN1 gene methylation is associated with age and internalizing symptoms in females with ASD. • Mitochondrial Dysfunction : Highlighted as a central feature in ASD pathology with sex-specific differences. • Significance : Emphasizes the need for sex-specific diagnostic tools and therapeutic approaches in ASD. • Future Research : Should focus on sex differences in genetic and epigenetic mechanisms underlying ASD to develop targeted interventions.