Altered DNA methylation and gene expression predict disease severity in patients with Aicardi-Goutieres syndrome

Aicardi-Goutie`res Syndrome (AGS) is a rare neuro-inflammatory disease characterized by increased expression of interferon-stimulated genes (ISGs). Disease-causing mutations are present in genes associated with innate antiviral responses. Disease presentation and severity vary, even between patients with identical mutations from the same family. This study investigated DNA methylation signatures in PBMCs to understand phenotypic heterogeneity in AGS patients with mutations in RNASEH2B. AGS patients presented hypomethylation of ISGs and differential methylation patterns (DMPs) in genes involved in neutrophil and platelet activation. Patients with mild phenotypes exhibited DMPs in genes involved in DNA damage and repair, whereas patients with severe phenotypes had DMPs in cell fate commitment and organ development associated genes. DMPs in two ISGs (IFI44L, RSAD2) associated with increased gene expression in patients with severe when compared to mild phenotypes. In conclusion, altered DNA methylation and ISG expression as biomarkers and potential future treatment targets in AGS.

Automated summary

This study investigated DNA methylation signatures in AGS patients to understand phenotypic heterogeneity. Hypomethylation of ISGs and differential methylation patterns in genes involved in neutrophil and platelet activation were observed. Patients with mild phenotypes had differential methylation patterns in genes involved in DNA damage and repair, while patients with severe phenotypes had differential methylation patterns in genes associated with cell fate commitment and organ development. DMPs in two ISGs (IFI44L, RSAD2) were associated with increased gene expression in severe cases compared to mild cases. Altered DNA methylation and ISG expression can be potential biomarkers and treatment targets in AGS.