Loss of function inRBBP5results in a syndromic neurodevelopmental disorder associated with microcephaly

Abstract

ABSTRACTPurposeEpigenetic dysregulation has been associated with many inherited disorders.RBBP5encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease.MethodsWe identify five unrelated individuals withde novoheterozygous pathogenic variants inRBBP5. Three truncating and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenicDrosophilamodels.ResultsBoth missense p.T232I and p.E296D variants affect evolutionarily conserved amino acids and are expected to interfere with the interface between RBBP5 and the histones. InDrosophila,ubiquitous overexpression of humanRBBP5is lethal in the larval developmental stage. Loss ofRbbp5leads to a reduction in brain size, and the human reference, p.T232I, or p.E296D variant transgenes fail to rescue loss ofRbbp5.Expression of either missense variant in anRbbp5null background results in a less severe microcephaly phenotype than the human reference, indicating both p.T232I and p.E296D variants are loss-of-function alleles.ConclusionDe novoheterozygous variants inRBBP5are associated with a syndromic neurodevelopmental disorder.Graphical abstract