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Indeed, studies of Kabuki syndrome type 1 (KS1) вЂ“ one of the most extensively studied MDEMs to date вЂ“ have begun unraveling the underpinnings of the neural ( Carosso et al., 2019), growth ( Fahrner et al., 2019), cardiac ( Ang et al., 2016), and immune defects ( Pilarowski et al., 2020 Zhang et al., 2015 Ortega-Molina et al., 2015) seen in this disorder. As a result, MDEMs may provide a unique lens into the causal relationship between epigenetic/transcriptomic variation and disease.

This implies the following causal chain underlying MDEM pathogenesis: a coding variant disrupts an epigenetic regulator, leading to downstream epigenomic abnormalities, which in turn give rise to the phenotype, likely by perturbing the transcriptome ( Figure 1A). MDEMs are caused by coding variants disrupting genes encoding for epigenetic regulators, which are generally very intolerant to loss-of-function variation ( Boukas et al., 2019). The recent advent and widespread clinical use of exome sequencing has led to the emergence of a novel class of Mendelian disorders, termed the Mendelian Disorders of the Epigenetic Machinery (MDEMs) ( Fahrner and Bjornsson, 2019). As a result, to date there are surprisingly few examples of causal relationships between epigenetic alterations and specific phenotypes notable exceptions include disorders of genomic imprinting ( Barlow and Bartolomei, 2014), disorders caused by repeat-expansion-induced aberrant promoter hypermethylation ( Sutcliffe et al., 1992 LaCroix et al., 2019), predisposition to some tumor types ( Sakatani et al., 2005 Rainier et al., 1993 Ogawa et al., 1993 Gazzoli et al., 2002), and вЂ“ in mice вЂ“ phenotypes caused by metastable epialleles ( Bertozzi and Ferguson-Smith, 2020 Rakyan et al., 2002). secondary consequences ( Rakyan et al., 2011 Lappalainen and Greally, 2017). While statistical associations between many diseases/traits and epigenetic changes have been detected, it is typically extremely challenging to rule out the influence of confounders such as the environment, and to determine whether these associations are primary causes vs. IntroductionДЄ long-standing and fundamental problem in epigenetics is the identification of specific epigenetic changes that causally mediate phenotypes through the alteration of transcriptional states. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals. Subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1, but not in KS2. We show that disruption of chromatin accessibility at promoters often disrupts downstream gene expression, and identify 587 loci and 264 genes with shared disruption across all three MDEMs. We develop a new approach for the overlap analysis and find extensive overlap primarily localized in gene promoters. To identify such shared alterations, we interrogate chromatin (ATAC-seq) and expression (RNA-seq) states in B cells from three MDEM mouse models (Kabuki type 1 and 2 and Rubinstein-Taybi type 1 syndromes). We hypothesize that this phenotypic convergence is a consequence of shared epigenetic alterations. Although each Mendelian Disorder of the Epigenetic Machinery (MDEM) has a different causative gene, there are shared disease manifestations.

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