Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities

Am J Hum Genet. 2020 Dec 3;107(6):1044-1061. doi: 10.1016/j.ajhg.2020.10.007. Epub 2020 Nov 6.


Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulfated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report bi-allelic pathogenic variants in HS2ST1 in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal, and renal development.

Keywords: 2-O-sulfate; 3’-phosphoadenosine 5’-phosphosulfate; extracellular matrix; glycosaminoglycan; iduronic acid; paxillin; syndrome; whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Biopsy
  • Bone and Bones / abnormalities*
  • Child
  • Child, Preschool
  • Corpus Callosum / pathology*
  • Developmental Disabilities / genetics*
  • Extracellular Matrix / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Family Health
  • Female
  • Fibroblasts / metabolism
  • Genetic Variation
  • Heparitin Sulfate / metabolism
  • Humans
  • Iduronic Acid / pharmacology
  • Infant, Newborn
  • Kidney / abnormalities*
  • Male
  • Pedigree
  • Phenotype
  • Sulfotransferases / genetics*
  • Syndrome
  • Urogenital Abnormalities / genetics


  • Iduronic Acid
  • Heparitin Sulfate
  • Extracellular Signal-Regulated MAP Kinases
  • Sulfotransferases
  • heparan-sulfate 2-sulfotransferase

Supplementary concepts

  • Renal Adysplasia