Surprisingly, in vitro histone methyltransferase assays and H3K27me3 analyses in cells revealed that at least two missense variants (p.A678G and p.Q731E) increase catalytic activity of EZH1, indicating that both EZH1 gain- and loss-of-function can lead to comparable NDD phenotypes. Here, EZH1 is linked to Neurodevelopmental delay.