Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. This implies that identifying abnormalities shared across multiple MDEMs could pinpoint locations where epigenetic variation is causally related to disease phenotypes. To test our hypothesis, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify a total of 463 loci and 249 genes commonly disrupted across the three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we propose that subtle expression alterations of multiple, directly relevant genes, collectively contributes to IgA deficiency in KS1 and RT. Our model predicts that KS2 does not have IgA deficiency and we confirm this pattern in mice. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.