Increased dosage of the brain-disease gene ARX affects transcriptional activity and chromatin remodelling and may clear up Intellectual Disability (ID) found in a male patient with a Xp21.3 duplication

Protein-coding mutations in Aristaless related homeobox (ARX) cause various forms of Neurodevelopmental diseases (NDDs) such as X-linked ID and epilepsy. Nevertheless, dosage sensitivity of ARX locus is an emerging question since it has been recently demonstrated that breakpoints in enhancer elements of ARX can alter its tissue-specific expression in the developing brain. On the other hand, the Xp21 region, where ARX maps, undergoes frequent genomic rearrangements detected in neurobehavioral phenotypes. We report the characterization of a novel interstitial Xp21.3 duplication detected by GCH Microarray.We compared clinical features and functional findings established in this XLID case to those identified in our cohort of ARX patients and discuss how unbalance dosages of this crucial neuronal TF, associated with both increased and diminished activity, may induce similar cognitive outcomes.