Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefit on the patients’ developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes. KCNQ2 encodes a voltage-gated potassium channel widely expressed in the central nervous system and is critically involved in the regulation of neuronal excitability. Here we engineer and characterise a new Kcnq2 DEE mouse model (K557E) based on the K556E variant discovered in a female patient with a milder form of DEE. While no significant biophysical changes were observed when the mutant channel was expressed in a heterologous system, the heterozygous knock-in mice showed a reduced survival rate and increased susceptibility to induced seizures. Electrophysiology recordings in brain slices revealed a hyperexcitable phenotype for cortical layer 2/3 pyramidal neurons with retigabine (K_V7 channel opener) able to rescue both the increased sensitivity to chemically- induced seizures in vivo and neuronal excitability ex vivo. Interestingly, whole brain RNA sequencing revealed numerous differentially expressed genes and biological pathways pointing at dysregulation of early developmental processes. Our study reports on a novel Kcnq2 DEE mouse model recapitulating aspects of the disease phenotype with the electrophysiological and transcriptomic analysis providing insights into KCNQ2 DEE mechanisms that can be leveraged for the future therapy development.