Using a genome-wide DNA methylation analysis, we and others have identified specific DNA methylation epi-signatures in the peripheral blood of patients with a number of genetic diseases that result from the disruption of epigenomic machinery, including alpha-thalassemia/mental retardation X-linked (ATRX) syndrome [8], Floating-Harbor syndrome [9], DNA methyltransferase 1 (DNMT1)-associated autosomal dominant cerebellar ataxia, deafness, and narcolepsy syndrome [10], along with Kabuki [11, 12] and Sotos syndromes [13]. The gene discussed is DNMT1; the disease is Sotos syndrome.