MDGA2 is a membrane-anchored glycosylphosphatidylinositol protein that functions as an excitatory synaptic suppressor with critical roles in nervous system development and synaptic regulation 1. At the molecular level, MDGA2 regulates glutamatergic synapse function through multiple mechanisms: it competes with BDNF for TrkB binding to suppress BDNF/TrkB signaling 2, interacts with EphB2 to block Ephrin-B1-mediated activation 1, and modulates neuroligin-2 at inhibitory synapses 3. MDGA2 stability is regulated by RPS23RG1, which antagonizes SORT1-mediated lysosomal degradation 4. Disease relevance is substantial: homozygous loss-of-function MDGA2 variants cause developmental and epileptic encephalopathy with infantile hypotonia, severe developmental delay, and intractable seizures 5. Heterozygous Mdga2 deficiency in mice produces autism-relevant behavioral changes and increased excitatory synaptic transmission 2. Additionally, elevated MDGA2 plasma levels are associated with increased lung adenocarcinoma risk 6, while MDGA2 polymorphisms correlate with harm avoidance personality traits 7. In cardiovascular contexts, miR-9-mediated MDGA2 suppression promotes endothelial cell proliferation and reduces apoptosis under hypertensive conditions 8, suggesting MDGA2 normally promotes cell death. These findings position MDGA2 as a therapeutic target for autism spectrum disorder and developmental encephalopathy.