title: Genetic heterogeneity and clinical variability in musculocontractural Ehlers-Danlos syndrome caused by impaired dermatan sulfate biosynthesis.
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.
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
authors.forename: Delfien
authors.initials: D
authors.lastname: Syx
authors.forename: Tim
authors.initials: T
authors.lastname: Van Damme
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: Merel C
authors.initials: MC
authors.lastname: Maiburg
authors.forename: Ingrid
authors.initials: I
authors.lastname: van de Laar
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.forename: Miguel
authors.initials: M
authors.lastname: Del Campo
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: Trinh
authors.initials: T
authors.lastname: Hermanns-Lê
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D002648:Child; D003094:Collagen / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003871:Dermatan Sulfate / Q000096:biosynthesis*; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005109:Extracellular Matrix / Q000378:metabolism; D019066:Facies; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D015238:Sulfotransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D005353:Fibronectins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D003871:Dermatan Sulfate; D003094:Collagen; D015238:Sulfotransferases; C438013:dermatan-4-sulfotransferase-1; C405383:DSE protein, human
keywords: CHST14; DSE; EDS; Ehlers-Danlos syndrome; dermatan 4-O-sulfotransferase-1; dermatan sulfate epimerase-1