Abstract
AbstractGenetic disruption of chromatin regulators is frequently found in neurodevelopmental disorders (NDDs). While chromatin regulators are attractive therapeutic targets, studies to determine their implication in the etiology of NDDs are limited, preventing advances in diagnosis and treatment strategies. Here, we uncover pathogenic variants in the chromatin modifier Enhancer of Zeste Homologue 1 (EZH1) as the cause of overlapping recessive and dominant NDDs in 17 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 (K27) methyltransferases of the Polycomb Repressive Complex 2 (PRC2). Unlike the other PRC2 subunits, which are associated with the pathogenesis of human cancers and developmental disorders, the implication of EZH1 in human development and disease is largely unknown. Using cellular models and biochemical studies, we demonstrate that recessive variants cause EZH1 loss of function (LOF), while dominant variants are all missense mutations that modify the catalytic activity of EZH1, thus generating a gain of function (GOF) effect. Consistent with a pathogenic effect, depletion or overexpression of EZH1 perturbs neuronal differentiation in the developing chick embryo neural tube. Furthermore, using human pluripotent stem cell (hPSC) derived neural cultures and forebrain organoids, we show that EZH1 LOF and GOF variants respectively delay and accelerate the schedule of cortical projection neuron generation. Our work identifies EZH1 LOF and GOF variants as the genetic basis of previously undefined NDDs and uncovers an essential role of EZH1 in regulating the timing of neurogenesis.