LARGE1 is a bifunctional glycosyltransferase with alpha-1,3-xylosyltransferase and beta-1,3-glucuronyltransferase activities 1. It catalyzes the processual polymerization of matriglycan, a linear glycan polymer with repeating [-3-Xylose-alpha-1,3-GlcA-beta-1-] units on alpha-dystroglycan (DAG1) 1, enabling high-affinity DAG1 binding to laminin G-like domain-containing extracellular matrix proteins 1. LARGE1 localizes to the cis/medial-Golgi apparatus where it functions downstream of B4GAT1-initiated primer synthesis, requiring phosphorylated core M3 and the dystroglycan N-terminal domain (DGN) for activity 21. Matriglycan dysfunction causes muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies (A6) or impaired intellectual development (B6) 1. LARGE1 mutations impair satellite cell function and skeletal muscle regeneration capacity 3. Emerging evidence suggests LARGE1 dysregulation associates with disease severity in spinal muscular atrophy, where elevated cerebrospinal fluid and serum LARGE1 correlates with treatment response to nusinersen 4. Additionally, LARGE1 serves as an entry factor for Lassa virus, with LARGE1 haplotypes associated with differential fatal outcome risk 5. Functional variant interpretation through saturation mutagenesis enables improved clinical classification of uncertain significance variants 6.