Trisomy 21 has also been associated with DNA hypomethylation in TMD/ML–DS, with downregulation of endothelin signaling and over-activity of insulin-like growth factor (IGF) signaling in DS-leukemia primary patient samples, iPSCs and murine models [62, 84, 87, 120], although the chromosome 21 genes and the underlying mechanisms associated with these molecular features remain largely unknown. This evidence concerns the gene IGF1 and Dravet syndrome.