Submission Details

C1GALT1C1 was first reported in relation to x-linked atypical hemolytic uremic syndrome 8 with rhizomelic short stature (AHUS8) in 2023 (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). C1GALT1C1 (also known as COSMC) is a highly evolutionary conserved gene mapped to chromosome Xq24 (Hadar et al., PMID: 36599939). It is a molecular chaperone required for the proper folding and full activity of T synthase, the enzyme that initiates complex O-glycans biosynthesis (Erger et al., PMID: 37216524). In humans, somatic loss-of-function variants in C1GALT1C1 have been associated with Tn polyagglutination syndrome. Two recent reports, including a de novo hemizygous missense mutation and a hemizygous germline loss of function variant have been reported to cause AHUS8 (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). The term COSMC-CDG has been suggested (Erger et al., PMID: 37216524). Common symptoms among the reported cases include a combination of thrombocytopenia, immune deficiency, developmental delay, short stature with short limbs, facial dysmorphisms and variable-onset acute kidney injury resembling aHU in hemizygous males. Females exhibit less pronounced clinical phenotypes in line with X-linked semidominant inheritance. Treatment with C5 inhibitors results in improvement of renal function (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). This gene-disease relationship is supported by relevant experimental evidence, including an animal model (Wang et al., PMID:20439703) and expression studies (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). Currently, the biological evidence is clear but more clinical evidence is necessary. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ClinGen Congenital Disorders of Glycosylation GCEP on January 2, 2025 (SOP Version 11).

C1GALT1C1 was first reported in relation to x-linked atypical hemolytic uremic syndrome 8 with rhizomelic short stature (AHUS8) in 2023 (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). C1GALT1C1 (also known as COSMC) is a highly evolutionary conserved gene mapped to chromosome Xq24 (Hadar et al., PMID: 36599939). It is a molecular chaperone required for the proper folding and full activity of T synthase, the enzyme that initiates complex O-glycans biosynthesis (Erger et al., PMID: 37216524). In humans, somatic loss-of-function variants in C1GALT1C1 have been associated with Tn polyagglutination syndrome. Two recent reports, including a de novo hemizygous missense mutation and a hemizygous germline loss of function variant have been reported to cause AHUS8 (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). The term COSMC-CDG has been suggested (Erger et al., PMID: 37216524). Common symptoms among the reported cases include a combination of thrombocytopenia, immune deficiency, developmental delay, short stature with short limbs, facial dysmorphisms and variable-onset acute kidney injury resembling aHU in hemizygous males. Females exhibit less pronounced clinical phenotypes in line with X-linked semidominant inheritance. Treatment with C5 inhibitors results in improvement of renal function (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). This gene-disease relationship is supported by relevant experimental evidence, including an animal model (Wang et al., PMID:20439703) and expression studies (Hadar et al., PMID: 36599939; Erger et al., PMID: 37216524). Currently, the biological evidence is clear but more clinical evidence is necessary. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on January 2, 2025 (SOP Version 11).