B3GALNT2 encodes a beta-1,3-N-acetylgalactosaminyltransferase that synthesizes the GalNAc-beta-1-3GlcNAc carbohydrate structure on N- and O-glycans, functioning as a glycosyltransferase without galactose or galactosaminyl transferase activity toward other substrates 1. The enzyme acts coordinately with GTDC2/POMGnT2 in the endoplasmic reticulum to modify alpha-dystroglycan (α-DG) by synthesizing a phosphorylated O-mannosyl trisaccharide essential for binding laminin G-like domain-containing extracellular proteins with high affinity 1. Loss of B3GALNT2 function severely reduces α-DG glycosylation and abolishes laminin binding despite partial residual enzymatic activity, supporting a critical functional threshold model 2. B3GALNT2 mutations cause alpha-dystroglycanopathy (α-DGP), a rare congenital muscular dystrophy characterized by variable severity ranging from limb girdle muscular dystrophy to Walker-Warburg syndrome with brain malformations, developmental delay, eye abnormalities, and congenital hydrocephalus 3456. Pathogenic variants include truncating mutations causing complete protein loss and missense mutations impairing enzymatic activity to 40-50% of wild-type levels 2. Clinical phenotypes encompass muscle-eye-brain disease, West syndrome, and sensorineural hearing loss, with genotype-phenotype correlations emerging from expanding case reports 6.