Patients with Kleefstra syndrome are characterized by a specific alteration of the epimethylation signature, largely overlapping that of the Wiedemann–Steiner syndrome (WDSTS) (Aref-Eshghi 2020), associated with variants, mostly of truncating type, in KMT2A, encoding another lysine-methyltransferase. This evidence concerns the gene KMT2A and Kleefstra syndrome.