Variants and pathogenetic mechanism
B4GALT7 variants responsible for the spondylodysplastic Ehlers-Danlos Syndrome type 1 (EDSSPD1 B4GALT7-related) phenotype are mostly hypomorphic missense variants, following an autosomal recessive mode of inheritance. While haploinsufficiency is not a known mechanism of disease, rare nonsense and frameshift variants have also been observed, either compound heterozygous with a pathogenic missense variant, or homozygous in at least one patient (Ritelli et al., Orphanet J. Rare Dis 2017), with no apparent genotype-phenotype correlations to date.
B4GALT7 encodes a glycosyltransferase involved in the synthesis of proteoglycans, complex macromolecules localized at cell membranes and in the extracellular matrix. They play an important role in the mechanical properties of several tissues, but also in cell signalling. Specifically, B4GALT7 catalyzes the second step in the synthesis of the tetrasaccharide linker connecting Serine residues on the proteoglycan peptidic core with the glycosaminoglycan (GAG) chains (see Figure). Biallelic deleterious variants associated with reduced enzyme activity lead to the defects in the structure and function of connective tissue observed in spEDS.
Genetic testing
An NGS panel specific for EDS would be advisable since it can help with the differential diagnosis, particularly during the first months of life, when some of the distinctive clinical signs may not have evolved yet.
If the spEDS subtype is specifically suspected, direct Sanger sequencing of the B4GALT7 and B3GALT6 genes is also a viable and cost-effective option (both genes feature relatively short coding regions). This could be considered especially if the radiological signs restrict the hypothesis to either gene (radioulnar synostosis for B4GALT7, severe progressive kyphoscoliosis and platyspondyly for B3GALT6).