Genetic Heterogeneity and Clinical Variability in Musculocontractural Ehlers–Danlos Syndrome Caused by Impaired Dermatan Sulfate Biosynthesis |
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| Authors: | Delfien Syx,Tim Van Damme,Sofie Symoens,Merel C. Maiburg,Ingrid van de Laar,Jenny Morton,Mohnish Suri,Miguel Del Campo,Ingrid Hausser,Trinh Hermanns‐Lê,Anne De Paepe,Fransiska Malfait |
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| Affiliation: | 1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium;2. University Medical Center Utrecht, Department of Medical Genetics, Utrecht, The Netherlands;3. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands;4. Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, United Kingdom;5. Nottingham Clinical Genetics Service, Nottingham City Hospital, Nottingham, United Kingdom;6. Area de Genetica Clinica y Molecular, Hospital Vall d ‘Hebron, Barcelona, Spain;7. Institute of Pathology, University Clinic Heidelberg, Heidelberg, Germany;8. Department of Dermatopathology, Liège University Hospital, Liège, Belgium |
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| Abstract: | Bi‐allelic variants in CHST14, encoding dermatan 4‐O‐sulfotransferase‐1 (D4ST1), cause musculocontractural Ehlers–Danlos syndrome (MC‐EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. 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 for this condition. DS‐epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC‐EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC‐EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1‐ as well as DS‐epi1‐deficient patients. However, in D4ST1‐deficiency, the decorin GAG is completely replaced by CS, whereas in DS‐epi1‐deficiency, 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. |
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| Keywords: | Ehlers– Danlos syndrome EDS CHST14 dermatan 4‐O‐sulfotransferase‐1 DSE dermatan sulfate epimerase‐1 |
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