We report 28 unrelated individuals, affected with neurodevelopmental abnormalities encompassing ID/DD, ASD, RTT-like features and seizures or developmental epileptic encephalopathy (DEE), in whom we have identified heterozygous de novo variants in GRIA2. Functional analyses reveal loss of function for the majority of the mutations, supporting GluA2 defects as a cause of NDDs with variable associated neurological phenotypes. This evidence concerns the gene GRIA2 and developmental and epileptic encephalopathy.