Luo, S., Wang, P.Y., Zhou, P., Zhang, W.J., Gu, Y.J., Liang, X.Y., Zhang, J.W., Luo, J.X., Zhang, H.W., Lan, S., Zhang, T.T., Yang, J.H., Sun, S.Z., Guo, X.Y., Wang, J.L., Deng, L.F., Xu, Z.H., Jin, L., He, Y.Y., Ye, Z.L., Gu, W.Y., Li, B.M., Shi, Y.W., Liu, X.R., Yan, H.J., Yi, Y.H., Jiang, Y.W., Mao, X., Li, W.L., Meng, H., Liao, W.P. (2025). Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders.  Am. J. Hum. Genet. 112(1): 87--105.

FBrf0261295

Research paper

EP400 encodes a core catalytic ATPase subunit of ATP-dependent chromatin remodeling complexes. The gene-disease association of EP400 is undetermined. In this study, we performed trio-based whole-exome sequencing in a cohort of 402 families with epilepsy and neurodevelopmental disorders (NDDs) and identified compound heterozygous EP400 variants in six unrelated individuals. Six additional EP400 individuals were recruited via the match platform of China, including two de novo heterozygous and four compound heterozygous variants. The individual with a heterozygous de novo frameshift variant presented with NDDs, while the others exhibited epilepsy and NDDs, explained by the damaged genetic dependence quantity. EP400 presented significantly higher excesses of variants in the individuals. Clustering analysis revealed that the majority paralogs of EP400 were associated with NDDs/epilepsy and co-expressed highly with EP400. Analysis of the spatiotemporal expression indicated that EP400 is highly expressed in the developing brain and cells during differentiation, indicating its vital role in neurodevelopment; EP400 is predominantly expressed in inhibitory neurons in the early stage but in excitatory neurons in the mature stage. The development-dependent expression pattern of neuron specificity explained the favorable outcome of epilepsy. Knockdown of EP400 ortholog in Drosophila caused significantly increased susceptibility to seizures and abnormal neuronal firing. The ep400 crispant zebrafish exhibited brain developmental abnormalities, poorer adaptability, lower response to stimulation, epileptic discharges, abnormal cellular apoptosis, and increased susceptibility to seizures. Transcriptome analysis showed that ep400 deficiency caused expressional dysregulation of 84 epilepsy/NDD-associated genes, including 11 highly dose-sensitive genes. This study identified EP400 as a causative gene of epilepsy/NDDs.

PMC11739926 (PMC) (EuropePMC)