The mechanistic hypotheses regarding trans-hypermethylation in DS due to trisomy 21 are well-articulated [3]; they suggest that the hypermethylation may be due to an increased dosage of chromosome 21 genes involved in methylation pathways per se (e.g., SLC19A1, FTCD, CBS, PRMT2, and DNMT3L) and/or due to abnormal patterns of particular transcription factors binding site (e.g., sites for CTCF and RUNX1) occupancies. Here, CTCF is linked to Dravet syndrome.