Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes

Marco Ritelli, Valeria Cinquina, Edoardo Giacopuzzi, Marina Venturini, Nicola Chiarelli, Marina Colombi

Research output: Contribution to journalArticlepeer-review


The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.
Original languageEnglish
Article number631
Issue number9
Publication statusPublished - 2019


  • *B3GALT6
  • *B3GAT3
  • *B4GALT7
  • *Desbuquois dysplasia
  • *Larsen-like syndrome
  • *XYLT1
  • *XYLT2
  • *linkeropathies
  • *spondylo-ocular syndrome
  • *spondylodysplastic Ehlers-Danlos syndrome
  • Adolescent
  • Antley-Bixler Syndrome Phenotype/*genetics/pathology
  • Arachnodactyly/*genetics/pathology
  • Bone Diseases/*congenital/genetics/pathology
  • Craniosynostoses/*genetics/pathology
  • Dwarfism/*genetics/pathology
  • Female
  • Glucuronosyltransferase/*genetics
  • Humans
  • Marfan Syndrome/*genetics/pathology
  • *Mutation
  • Osteochondrodysplasias/*genetics/pathology
  • *Phenotype
  • Skin Diseases, Genetic/*genetics/pathology


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