Barbosa, M.Joshi, R.Garg, P.Martin-Trujillo, A.Patel, N.Jadhav, B.Watson, C.Gibson, W.Chetnik, K.Tessereau, C.Mei, H.De Rubeis, S.Reichert, J.Lopes, F.Vissers, L.Kleefstra, T.Grice, D.Edelmann, L.Soares, G.Maciel, P.Brunner, H.Buxbaum, J.Gelb, B.Sharp, A.2020-02-032020-02-032018-05-25Nat Commun. 2018 May 25;9(1):20642041-1723http://hdl.handle.net/10400.16/2305Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance.engjournal article10.1038/s41467-018-04540-x