Genetic heterogeneity and clinical variability in musculocontractural ehlers-danlos syndrome caused by impaired dermatan sulfate biosynthesis

Bi-allelic variants in CHTS-14, encoding dermatan 4-O sulfotransferase-1(D4ST-1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures and developmental abnormalities. Recently, the identification of bi-allelic variants in DSE, encoding dermatan-sulfate epimerase-1(DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity of this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondoitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and a second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of a dermal DS protoglycan decorin is impaired in fibroblasts from D4ST1, as well as DS-epi1-deficient patients. However, D4ST1-deficiency, decorin GAG is completely replaced by CS, whereas in DS-epi1-deficency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation and connective tissue integrity.Methusalem Gran