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Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses
  1. Sali M K Farhan1,2,
  2. Jian Wang1,
  3. John F Robinson1,
  4. Asuri N Prasad3,4,
  5. C Anthony Rupar2,4,5,
  6. Victoria M Siu2,4,5,
  7. FORGE Canada Consortium,
  8. Robert A Hegele1,2
  1. 1Robarts Research Institute, London, Ontario, Canada
  2. 2Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
  3. 3Division of Clinical Neurological Sciences, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada
  4. 4Children's Health Research Institute, London, Ontario, Canada
  5. 5Medical Genetics Program, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada
  1. Correspondence to Professor Robert A Hegele, Blackburn Cardiovascular Genetics Laboratory, 4288A-1151 Richmond St North, Robarts Research Institute, Western University, London, Ontario, Canada N6A 5B7; hegele{at}


Background Heparan sulfate proteoglycans are vital components of the extracellular matrix and are essential for cellular homeostasis. Many genes are involved in modulating heparan sulfate synthesis, and when these genes are mutated, they can give rise to early-onset developmental disorders affecting multiple body systems. Herein, we describe a consanguineous family of four sibs with a novel disorder, which we designate as seizures-scoliosis-macrocephaly syndrome, characterised by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction.

Methods Our application of autozygosity mapping and whole-exome sequencing allowed us to identify mutations in the patients. To confirm the autosomal-recessive mode of inheritance, all available family members were genotyped. We also studied the effect of these mutations on protein expression and function in patient cells and using an in vitro system.

Results We identified two homozygous mutations p.Met87Arg and p.Arg95 Cys in exostosin 2, EXT2, a ubiquitously expressed gene that encodes a glycosyltransferase required for heparan sulfate synthesis. In patient cells, we observed diminished EXT2 expression and function. We also performed an in vitro assay to determine which mutation has a larger effect on protein expression and observed reduced EXT2 expression in constructs expressing either one of the mutations but a greater reduction when both residues were mutated.

Conclusions In short, we have unravelled the genetic basis of a new recessive disorder, seizures-scoliosis-macrocephaly syndrome. Our results have implicated a well-characterised gene in a new developmental disorder and have further illustrated the spectrum of phenotypes that can arise due to errors in glycosylation.

  • Whole-exome sequencing
  • Heparan sulfate
  • EXT2
  • NDST1
  • Intellectual disability

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