The functional consequences of mutations within DNMT1, DNMT3B and DNMT3A, which cause monogenic human diseases and rare cancers, e.g. DNMT1 complex disorders (HSAN1E) [42, 43], DNMT3B (ICF syndrome) [44, 45] and DNMT3A (Tatton Brown Rahman syndrome) [46, 47], are proposed to be dependent on mutation type and the extent they cause a reduction in gene function or expression, i.e. the degree of hypomorphism. Here, DNMT3B is linked to ICF syndrome.