Epilepsy is a common neurological disorder with age-dependent seizures, which includes developmental and epileptic encephalopathy (DEE), a severe form of epilepsy. This study identified ZFHX3 as a pathogenic gene of DEE and partial epilepsy. All patients with ZFHX3 variants achieved seizure-free after appropriate treatment. Studies in fly, mouse, and human all showed that ZFHX3 is highly expressed in the embryonic stage and decreased dramatically after birth, potentially explaining the evolutionary course of the illness. Identification of ZFHX3 as a genetic cause of epilepsy/DEE and disclosing of the evolutionary mechanism of disease are potentially helpful for management of patients. (By Prof. Yong-Hong Yi, https://jmg.bmj.com/content/early/2024/03/20/jmg-2023-109725 )