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Am J Med Genet A. 2017 Mar;173(3):712-715. doi: 10.1002/ajmg.a.37621.

A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy-Expanding NDST1 syndrome.

Armstrong L1,2,3,4, Tarailo-Graovac M3,4,5,6, Sinclair G2,3,4, Seath KI1,5, Wasserman WW3,4,5,6, Ross CJ3,4,5,6,7, van Karnebeek CD3,4,5,7,8.

Author information

Provincial Medical Genetics Program, B.C. Women's Hospital & Health Centre, Vancouver, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.
Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada.
Department of Medical Genetics, B.C. Women's Hospital & Health Centre, Vancouver, Canada.
Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
Department of Pediatrics, University of British Columbia, Vancouver, Canada.
Department of Pediatrics, Academic Medical Centre, Amsterdam, The Netherlands.


NDST1 encodes an enzyme involved in the first steps in the synthesis of heparan sulfate chains, proteoglycans that are regulators found on the cell surface and in the extracellular matrix. Eight individuals homozygous for one of four family-specific missense mutations in the sulfotransferase domain of the enzyme have been described. They have intellectual disability. Some additionally had hypotonia, ataxia. seizures, and/or short stature, but none had history of respiratory problems. No humans with homozygous null mutations are known. ndst1b (orthologous to NDST1) morpholino knockdown in zebrafish (Danio rerio) causes delayed development, craniofacial cartilage abnormalities, shortened body and pectoral fin length. Ndst1 homozygous null mice have craniofacial abnormalities and die within the first 10 h of life of respiratory failure. We report a girl upon whom deep phenotyping, extensive genetic and biochemical investigations, and exome sequencing were performed. She had cranial nerves dysfunction, gastroesophageal reflux, history of a seizure, ataxia, developmental delays, head sparing failure to thrive, and minor malformations including distinctive facial features and a bifid uvula. Compound heterozygous mutations in NDST1 were identified, in the heparan sulfate N deacetylatase domain of one allele and the sulfotransferase domain of the other allele. This report expands the phenotypic spectrum of Ndst1 deficiency in humans.


autosomal recessive; intellectual disability; neural crest; pharyngeal arch; respiratory insufficiency; whole exome sequencing

[Indexed for MEDLINE]

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