HAPLOINSUFFICIENCY IN THE ENHANCER OF POLYCOMB HOMOLOGUE 1 (<EM>EPC1</EM>) GENE LEADS TO A NEURODEVELOPMENTAL SYNDROME AND CORTICAL CIRCUIT DYSFUNCTION

Neurodevelopmental disorders frequently arise from disruptions in epigenetic regulators, yet the contribution of the NuA4/TIP60 acetyltransferase and remodeling machinery to human brain development remains poorly defined. Here, we identify recurrent de novo heterozygous truncating variants in EPC1, a core scaffolding subunit of NuA4/TIP60, in five unrelated individuals presenting with early‑onset neurodevelopmental syndromes. Structural modelling of the human NuA4/TIP60 complex revealed that all patient variants eliminate the EPC1 region required for interaction with the EP400 remodeling module, thereby uncoupling histone H4 acetylation from ATP‑dependent histone‑variant exchange. To investigate the functional consequences of EPC1 loss, we established C. elegans and mouse models of EPC1 haploinsufficiency. Heterozygous epc‑1 mutant worms displayed impaired locomotion and motor coordination, demonstrating conserved EPC1 dosage sensitivity across species. In mice, Epc1^+/– mutants exhibited reduced Epc1 transcript levels, histone H4 hypoacetylation in the cerebral cortex, and widespread transcriptional dysregulation characterized by abnormal regulation of developmental gene expression programs. Behaviourally, Epc1^+/– mice showed deficits in social memory, spatial working memory, contextual fear recall, motor coordination, and cognitive flexibility, accompanied by imbalances in specific populations of excitatory and inhibitory neurons. Together, these findings establish EPC1 haploinsufficiency as a novel cause of human neurodevelopmental disease, and demonstrate that perturbation of the EPC1‑dependent integration of HAT and chromatin‑remodeling functions disrupts cortical development, circuit composition, and cognitive function.