DLG4 (discs large MAGUK scaffold protein 4) encodes postsynaptic density protein-95 (PSD-95), a critical postsynaptic scaffolding protein that organizes synaptic architecture and regulates excitatory synaptic function 1. DLG4 provides a molecular platform for clustering NMDA receptors, AMPA receptors, and other essential synaptic proteins at the postsynaptic membrane, thereby controlling synaptic plasticity and neuronal communication 2. The protein mediates phase separation of postsynaptic density complexes, enabling formation of concentrated protein-enriched compartments necessary for synaptic organization 2. DLG4 coordinates synaptic stability through interactions with kinases and palmitoyltransferases that regulate membrane localization of signaling molecules [UniProt summary]. Loss-of-function DLG4 variants cause DLG4-related synaptopathy, a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, autism spectrum disorder, and attention-deficit hyperactivity disorder 1. Approximately 50% of affected individuals develop epilepsy, with over 25% experiencing developmental epileptic encephalopathy with spike-wave activation during sleep 3. Most pathogenic variants (39 of 45 identified) are loss-of-function mutations occurring de novo 1, disrupting the precise synaptic protein assembly required for normal brain development and cognitive function. DLG4 dysfunction highlights the critical importance of postsynaptic scaffolding in preventing neurodevelopmental disease.