Submission Details

B3GALT6 was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2013 (Nakajima et al., PMID: 23664117). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Al-Gazali syndrome (OMIM:609465), Ehlers-Danlos syndrome, spondylodysplastic type, 2 (OMIM:615349), and Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures (OMIM:271640) and curated under the disease entity congenital disorder of glycosylation. 22 unique variants (start loss, missense, in-frame indel, and frameshift) that have been reported in 17 probands in 7 publications (PMIDs: 23664117, 25149931, 28649518, 23664118, 29230159, 34529350, 29443383) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, two reports of monogenic (autosomal dominant) inheritance have been published in the literature, but there is not enough evidence to rule out a second variant in trans (PMIDs: 23664117, 35734427). The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by an animal model (PMID: 33363150). In summary, there is definitive evidence supporting the relationship between B3GALT6 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 Glycosylaton GCEP on the meeting date January 15, 2025 (SOP Version 11).