Finally, targeting epigenetic editors to specific regions in the genome will not be beneficial if the epigenetic alterations are caused by mutations in trans-acting factors with genome- wide disruptions as in ICF1 (DNMT3B), FSHD2 (SMCHD1), SOTOS (NSD1), RETT (MecP2), and many other epigenetically regulated syndromes. Here, SMCHD1 is linked to Down syndrome.