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

Genes (Basel). 2019 Aug 21;10(9):631. doi: 10.3390/genes10090631.


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.

Keywords: B3GALT6; B3GAT3; B4GALT7; Desbuquois dysplasia; Larsen-like syndrome; XYLT1; XYLT2; linkeropathies; spondylo-ocular syndrome; spondylodysplastic Ehlers-Danlos syndrome.

Publication types

  • Case Reports
  • Review

MeSH terms

  • Adolescent
  • Antley-Bixler Syndrome Phenotype / genetics*
  • Antley-Bixler Syndrome Phenotype / pathology
  • Arachnodactyly / genetics*
  • Arachnodactyly / pathology
  • Bone Diseases / congenital*
  • Bone Diseases / genetics
  • Bone Diseases / pathology
  • Craniosynostoses / genetics*
  • Craniosynostoses / pathology
  • Dwarfism / genetics*
  • Dwarfism / pathology
  • Female
  • Glucuronosyltransferase / genetics*
  • Humans
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / pathology
  • Mutation*
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Phenotype*
  • Skin Diseases, Genetic / genetics*
  • Skin Diseases, Genetic / pathology


  • B3GAT3 protein, human
  • Glucuronosyltransferase

Supplementary concepts

  • Gerodermia osteodysplastica
  • Larsen Syndrome
  • Shprintzen Golberg craniosynostosis