ROBO3 is a guidance receptor that plays a crucial role in axon guidance during central nervous system development, particularly in facilitating commissural axon crossing at the midline 1. The protein acts as a multifunctional regulator of pathfinding, simultaneously mediating repulsion signals, inhibiting SLIT-mediated repulsion through ROBO1/ROBO2, and facilitating Netrin-1 attraction 1. In spinal cord development, ROBO3 guides commissural axons by preventing premature sensitivity to Slit proteins, allowing proper midline crossing 1. Pathogenic variants in ROBO3 cause horizontal gaze palsy with progressive scoliosis type 1 (HGPPS1), an autosomal recessive disorder characterized by congenital absence of horizontal eye movements and progressive scoliosis 23. This condition results from failure of corticospinal and somatosensory axon tracts to decussate in the medulla 4. Over 60 ROBO3 pathogenic variants have been identified in nearly 100 patients, with the gene located on chromosome 11-25 34. Recent studies suggest ROBO3 may have broader roles beyond neuronal development, including potential involvement in immune-related processes and as a biomarker in certain diseases 5. The protein represents an evolutionarily conserved guidance receptor with distinct mammalian-specific functions 1.