LFNG (Lunatic Fringe) is an O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase that modulates Notch signaling through glycosylation of O-linked fucose residues on EGF-like repeats in Notch extracellular domains 1. LFNG specifically inhibits NOTCH1 activation by JAG1 while enhancing activation by DLL1, and decreases JAG1 binding to NOTCH2 2. The enzyme is essential for somite segmentation and patterning during development 3. Bi-allelic LFNG loss-of-function variants cause spondylocostal dysostosis 3 (SCDO), characterized by vertebral and rib segmentation defects 4. The mutational spectrum includes coding and non-coding variants across LFNG exons 3. Beyond developmental roles, LFNG has significant oncogenic functions. High LFNG expression associates with poor prognosis across multiple cancer types, particularly pancreatic adenocarcinoma 5. In pancreatic cancer, Lfng-expressing centroacinar cells are preferentially targeted by oncogenic Kras and p53 mutations; LFNG deletion blocks tumor initiation, and LFNG upregulation promotes progression 6. In hepatoblastoma, LFNG overexpression promotes cell migration and invasion through immune microenvironment modulation 7. LFNG deletion in breast cancer promotes deregulated Notch activation and Met amplification in basal-like tumors 8.