Recent advances in mass spectrometry has empowered unbiased global analysis of site-specific O-GalNAc glycosylation. Despite thousands of sites being identified, significant technical hurdles remain, particularly in the delineation of fully extended, larger O-GalNAc glycans on heavily O-glycosylated mucin domain. Current approaches require simplification of the O-GalNAc glycans either by genetic means or glycosidase treatments to allow unambiguous sequencing of the derived O-glycopeptides. In contrast, a full mapping of the O-GalNAc glycomic complexity still necessitates a detailed analysis of the released glycans. Chromatographic resolution and multistage fragmentation coupled with judicious choice of chemical derivatization are key to increase the analytical precision and glycomic coverage depth, which should be duly considered along with attainable sensitivity and throughput for meaningful glycobiology applications.
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