<scp> <i>C1GALT1C1</i> </scp> ‐Associated Mosaic Disorder of Glycosylation in a Female

Cosmc, encoded by the X-linked C1GALT1C1, is a molecular chaperone in the endoplasmic reticulum and a master regulator of O-glycosylation of mammalian glycoproteins. Recently, we described a germline mutation in C1GALT1C1 in two male patients, giving rise to a congenital disorder of glycosylation-COSMC-CDG. Here, we have identified a female patient with a de novo mosaic variant in C1GALT1C1 (c.202C>T, p.Arg68*), which results in a truncated and nonfunctional form of Cosmc (Cosmc-R68). The patient is mosaic, as ~27% of her buccal cells carry the mutation. The patient is now a 5-year old who presented with nonimmune hydrops fetalis. As Cosmc is essential for the generation of normal O-glycans through regulating T-synthase activity, thereby enabling the formation of the universal Core 1 O-glycan Galβ1-3GalNAcα1-Ser/Thr (T-antigen), the loss of Cosmc leads to the expression of the unusual precursor O-glycan termed Tn-antigen (CD175) (GalNAcα1-Ser/Thr). Owing to the mutational mosaicism, only a significant minority of cells would exhibit abnormal O-glycosylation. Analysis of red blood cells (RBCs), leukocytes, and serum from this patient indicated reduced expression of Cosmc and T-synthase proteins and lower T-synthase activity. Consistent with these findings, we observed reduced normal O-glycans in serum glycoproteins and RBCs from the patient, along with elevated expression of the Tn-antigen in serum glycoproteins compared to controls. This case represents the first description of a true mosaic loss-of-function variant in C1GALT1C1, that is, one that occurred postzygotically during embryogenesis, and raises interesting questions about the role of O-glycosylation during fetal development and its consequences on the clinical presentation.