Therefore, we suggest a model (Fig. 5) where the reduction in the levels of H3K36me2 and/or H3K36me3, caused by a proposed decrease in H3K36 methylation maintenance during aging or NSD1 function in Sotos syndrome, could lead to hypomethylation in many genomic regions (because DNMT3A is recruited less efficiently) and hypermethylation in DMVs (because of the higher availability of DNMT3A). The gene discussed is DNMT3A; the disease is Sotos syndrome.