WDFY3 is an autophagy scaffolding protein essential for selective macroautophagy and brain development. It functions as an adapter linking ubiquitinated proteins destined for degradation to core autophagic machinery, including ATG5-ATG12-ATG16L and LC3, facilitating the formation and clearance of cytoplasmic ubiquitin-containing inclusions 1. WDFY3 regulates brain size through Wnt pathway control via DVL3 aggregate removal and is critical for axonal tract formation and neural cell guidance responses 2. In macrophages, WDFY3 mediates efferocytosis (clearance of apoptotic cells) by facilitating actin disassembly and lysosomal acidification through LC3 lipidation, thereby maintaining immune homeostasis and suppressing autoimmune responses 34. Clinically, heterozygous WDFY3 loss-of-function variants cause neurodevelopmental disorders with macrocephaly through Wnt pathway downregulation, while PH-domain variants paradoxically cause microcephaly via pathway upregulation 5. De novo mutations in WDFY3 are among the most prevalent in autism spectrum disorder cohorts, with recurrent mutations identified in Chinese ASD populations 67. These findings establish WDFY3 as a critical regulator of both neuronal development and immune homeostasis, with variants causing neurodevelopmental delay and intellectual disability.