DSCAM (Down Syndrome Cell Adhesion Molecule) is a neuronal cell adhesion molecule encoded on chromosome 21 that mediates self-avoidance and synaptic specificity in the developing nervous system. Primary function involves promoting repulsion between neuronal processes of the same cell or cell subtype to establish orderly dendritic arborization and maintain mosaic spacing in retinal networks. DSCAM acts as a netrin receptor for axon guidance and signals through MAPK8 and p38 activation, promoting lamina-specific synaptic connectivity via homophilic interactions in retinal interneurons and ganglion cells [UniProt annotations]. At the molecular level, DSCAM regulates the PAK1 pathway, with pathway dysregulation contributing to developmental abnormalities 1. Clinically, DSCAM has significant relevance to neurodevelopmental disorders. Recurrent de novo loss-of-function mutations in DSCAM are among the most prevalent autism spectrum disorder (ASD) risk variants, identified in approximately 1-2% of ASD patients in large cohorts 23. In Down syndrome, DSCAM gene dosage imbalance (trisomy 21) leads to DSCAM/PAK1 pathway hyperactivation, causing neurogenesis deficits and reduced cortical organoid size; CRISPR-based pathway suppression reverses these developmental abnormalities 1. DSCAM exhibits remarkable isoform diversity in invertebrates (tens of thousands of splice variants) but limited diversity in vertebrates, reflecting evolutionary specialization of neuronal wiring mechanisms 45.