Identification of rare de novo epigenetic variations in congenital disorders

Mafalda Barbosa, Ricky S. Joshi, Paras Garg, Alejandro Martin-Trujillo, Nihir Patel, Bharati Jadhav, Corey T. Watson, William Gibson, Kelsey Chetnik, Chloe Tessereau, Hui Mei, Silvia Rubeis, Jennifer Reichert, Fatima Lopes, Lisenka E. L. M. Vissers, Tjitske Kleefstra, Dorothy E. Grice, Lisa Edelmann, Gabriela Soares, Patricia Maciel, Han G. Brunner, Joseph D. Buxbaum, Bruce D. Gelb and Andrew J. Sharp ()
Additional contact information
Mafalda Barbosa: Icahn School of Medicine at Mount Sinai
Ricky S. Joshi: Icahn School of Medicine at Mount Sinai
Paras Garg: Icahn School of Medicine at Mount Sinai
Alejandro Martin-Trujillo: Icahn School of Medicine at Mount Sinai
Nihir Patel: Icahn School of Medicine at Mount Sinai
Bharati Jadhav: Icahn School of Medicine at Mount Sinai
Corey T. Watson: Icahn School of Medicine at Mount Sinai
William Gibson: Icahn School of Medicine at Mount Sinai
Kelsey Chetnik: Ramapo College of New Jersey
Chloe Tessereau: Icahn School of Medicine at Mount Sinai
Hui Mei: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Silvia Rubeis: Icahn School of Medicine at Mount Sinai
Jennifer Reichert: Icahn School of Medicine at Mount Sinai
Fatima Lopes: University of Minho
Lisenka E. L. M. Vissers: Donders Institute for Brain, Cognition and Behaviour
Tjitske Kleefstra: Donders Institute for Brain, Cognition and Behaviour
Dorothy E. Grice: Icahn School of Medicine at Mount Sinai
Lisa Edelmann: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Gabriela Soares: Center for Medical Genetics Dr. Jacinto Magalhães, Porto Hospital Center
Patricia Maciel: University of Minho
Han G. Brunner: Donders Institute for Brain, Cognition and Behaviour
Joseph D. Buxbaum: Icahn School of Medicine at Mount Sinai
Bruce D. Gelb: Icahn School of Medicine at Mount Sinai
Andrew J. Sharp: Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04540-x

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