Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional disruptions

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNMT3A, a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a DNMT3A P900L/+ mouse mimicking a mutation with mild-to-moderate severity, and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes which may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease. Overall design: Low and Hi-depth whole genome bisulfite sequencing (WGBS) of mouse cerebral cortex from 8-week WT and DNMT3A mutant mice Low-depth whole genome bisulfite sequencing (WGBS) of mouse brain region tissue from 8-week WT and DNMT3A mutant mice Chromatin immunoprecipitation DNA sequencing (ChIP-seq) for histone modification H3K27ac in 8-week wildtype and DNMT3A mutant mouse cerebral cortex Comparative gene expression profiling analysis of total RNA-seq data from 8-week WT and DNMT3A mutant mouse cerebral cortex Chromatin immunoprecipitation DNA sequencing (ChIP-seq) for MeCP2 in 8-week wildtype and DNMT3A mutant mouse cerebral cortex