Profiling Genome-Wide DNA Methylation in Children with Autism Spectrum Disorder and in Children with Fragile X Syndrome

Abstract

Autism spectrum disorder (ASD) is an early onset, developmental disorder whose genetic cause is heterogeneous and complex. In total, 70% of ASD cases are due to an unknown etiology. Among the monogenic causes of ASD, fragile X syndrome (FXS) accounts for 2–4% of ASD cases, and 60% of individuals with FXS present with ASD. Epigenetic changes, specifically DNA methylation, which modulates gene expression levels, play a significant role in the pathogenesis of both disorders. Thus, in this study, using the Human Methylation EPIC Bead Chip, we examined the global DNA methylation profiles of biological samples derived from 57 age-matched male participants (2–6 years old), including 23 subjects with ASD, 23 subjects with FXS with ASD (FXSA) and 11 typical developing (TD) children. After controlling for technical variation and white blood cell composition, using the conservatory threshold of the false discovery rate (FDR ≤ 0.05), in the three comparison groups, TD vs. AD, TD vs. FXSA and ASD vs. FXSA, we identified 156, 79 and 3100 differentially methylated sites (DMS), and 14, 13 and 263 differential methylation regions (DMRs). Interestingly, several genes differentially methylated among the three groups were among those listed in the SFARI Gene database, including the PAK2, GTF2I and FOXP1 genes important for brain development. Further, enrichment analyses identified pathways involved in several functions, including synaptic plasticity. Our preliminary study identified a significant role of altered DNA methylation in the pathology of ASD and FXS, suggesting that the characterization of a DNA methylation signature may help to unravel the pathogenicity of FXS and ASD and may help the development of an improved diagnostic classification of children with ASD and FXSA. In addition, it may pave the way for developing therapeutic interventions that could reverse the altered methylome profile in children with neurodevelopmental disorders.

The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype

“…PAK1 expression is activated via FOXO and E2F2 transcription factors and is inhibited by Rb (de la Torre-Ubieta et al, 2010;Sosa-García et al, 2015). PAK2 transcriptional regulation is still an understudied subject, however, PAK2 was found as differentially methylated in children with ASD (Jasoliya et al, 2022). PAK3 expression is inhibited by Notch, ZEB1, SP8/9 and DLX1/2 transcription factors, highlighting its role in the proneural pathway (Souopgui, 2002;Cobos et al, 2007;Liu et al, 2019;Shen et al, 2019;Wei et al, 2019).…”

DNA Methylation Biomarkers for Young Children with Idiopathic Autism Spectrum Disorder: A Systematic Review

“…By using a Benjamini-Hochberg multiple-test correction, 156, 79, and 3100 DMPs, and 14, 13, and 263 DMRs among TD vs. ASD, TD vs. FXSA and ASD vs. FXSA, respectively, were identified. Two genes that were differentially methylated between TD and ASD, namely, PAK2 and FANCD2, were among those listed in the SFARI Gene database as being previously associated with ASD [43].…”