ARHGEF9 encodes collybistin, a Cdc42 guanine nucleotide exchange factor that functions as a critical regulator of inhibitory GABAergic synapse organization. The protein acts as a scaffolding molecule that promotes gephyrin clustering at the postsynaptic density 1 and directly interacts with neuroligin-2 and the α2 subunit of GABAA receptors to coordinate inhibitory synapse assembly 2. ARHGEF9 mutations cause developmental and epileptic encephalopathy (DEE8), an X-linked condition characterized by severe, often treatment-resistant seizures, developmental delay, intellectual disability, autism spectrum features, and EEG abnormalities 34. Pathogenic variants lead to impaired GABAergic synaptic transmission through multiple mechanisms: reduced gephyrin phosphorylation and clustering 5, loss of functional inhibitory synapses at the axon initial segment 1, and defective inhibitory synaptic density in prefrontal cortex 5. These structural and functional deficits converge to disrupt action potential generation and circuit inhibition. Clinically, approximately 40 cases of ARHGEF9-related DEE have been reported, with valproic acid and levetiracetam demonstrating efficacy in some cases 4. Beyond neurological disease, ARHGEF9 functions as a tumor suppressor in gastric cancer and glioma through distinct pathways 67, expanding its biological roles beyond synapse regulation.