Escape genes from X-chromosome inactivation: new insights into candidate genes for intellectual disability in females

X-chromosome inactivation (XCI) is a dosage compensation mechanism in female mammals. Given that the Xchromosome harbours numerous genes implicated in cognitive function, variants in these genes can affect neurodevelopment and contribute to Intellectual Disability (ID). While research on ID has predominantly focused on males due to their hemizygous Xchromosome state, females, though often presenting with milder symptoms, may be affected by escape genes that evade XCI and influence the phenotype. This study investigated the role of escape genes in female ID. We employed data mining to analyse X-chromosome genes based on their XCI status, followed by functional enrichment analyses. Additionally, we conducted co-expression module evaluations in the main brain regions associated with ID and a protein-protein interaction (PPI) network analysis. We identified 31 significant modules linking XCI escape genes with ID-associated genes. The PPI network analysis further revealed direct interactions between the products of 25 genes and ID-related proteins. Five new candidate genes (RBMX2, PNPLA4, UBA1, RPS4X, and EIF1AX) were identified, four linked to known ID pathways. This study underscores the importance of escape genes in the context of female ID and paves the way for future experimental validation and molecular investigations into the functions of these genes.