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Identification of rare de novo epigenetic variations in congenital disorders

Publication . 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.

Certain 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.

2018-05-25Journal article

Open access