Here, we focused on the latest findings linking ncRNAs into the molecular and neural phenotypical defects of human disorders with deficiencies in (i) epigenetic modifiers, like MeCP2 (methyl-CpG-binding-protein-2) for the Rett syndrome (RTT) and DNMT3B (DNA-methyltrasferase-3B) for the Immumodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome (Type1) or (ii) in the establishment of DNA methylation signature, as for the imprinting disorders (Figure 1). The gene discussed is DNMT3B; the disease is ICF syndrome.