Submission Details

A4GALT was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2000 (Steffensen et al., PMID: 10747952). A4GALT-congenital disorder of glycosylation presents as the blood group phenotype p null. Persons affected with this condition may present with no phenotype beyond abnormal agglutination in standard blood group serological testing or may present with recurrent spontaneous abortion or congenital hemolytic anemia. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in molecular mechanism. Therefore, the following disease entities have been split into multiple disease entities, congenital disorder of glycosylation and NOR polyagglutination syndrome. The split curation for autosomal recessive NOR polyagglutination syndrome will be curated separately. 14 variants (missense, in-frame indel, nonsense, frameshift) that have been reported in 13 probands in 6 publications (PMIDs: 12823750, 15142124, 10747952, 10993874, 11896312, 27612185) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by in vitro functional assays. (PMIDs: 23927681, 18067504). In summary, there is definitive evidence supporting the relationship between A4GALT and autosomal recessive congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date May 21, 2025 (SOP Version 11).