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Epigenetic and genetic mechanisms regulate the establishment and maintenance of gene expression in its proper context. Recent genome-wide mapping approaches have identified DNA methylation (DNAm) signatures in patients clinically diagnosed with syndromes manifesting as developmental disabilities with intellectual impairments. Here, we review recent studies in which these DNA methylation signatures have enabled highly sensitive and specific screening of such individuals and have clarified ambiguous cases where subjects present with genetic sequence variants of unknown clinical significance (VUS). We propose that these episignatures be considered as echoes and/or legacies of the initiating mutational events within proteins of the so-called epigenetic machinery. As well, we discuss approaches to directly confirm the functional consequences and the implications of these episignatures to patient …