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

Aicardi-Goutières 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...

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Published in:Clinical immunology (Orlando, Fla.) Fla.), 2023-04, Vol.249, p.109299-109299, Article 109299
Main Authors: Garau, Jessica, Charras, Amandine, Varesio, Costanza, Orcesi, Simona, Dragoni, Francesca, Galli, Jessica, Fazzi, Elisa, Gagliardi, Stella, Pansarasa, Orietta, Cereda, Cristina, Hedrich, Christian M.
Format: Article
Language:English
Subjects:
Aicardi-Goutières syndrome
Autoimmune Diseases of the Nervous System - genetics
Biomarker
Biomarkers
Case-Control Studies
DNA Methylation
Gene Expression
Interferon
Interferons - genetics
ISG
Mutation
Nervous System Malformations - genetics
Phenotype
RNASEH2B
Severity of Illness Index
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Summary:Aicardi-Goutières 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. •Aicardi-Goutières Syndrome (AGS) patients with the RNASEH2B p.A177T mutation exhibit variable disease severity.•DNA methylation profiles in PBMCs separate AGS patients and controls, and “severe” from “mild” AGS.•Molecular scores based on type I IFN expression or DNA methylation associate with disease severity.•Findings from this study may inform future molecular patient stratification and individualized care.
ISSN:1521-6616
1521-7035
DOI:10.1016/j.clim.2023.109299