DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation

Am J Hum Genet. 2012 Feb 10;90(2):363-8. doi: 10.1016/j.ajhg.2011.12.024. Epub 2012 Feb 2.


Congenital disorders of glycosylation (CDG) are inherited autosomal-recessive diseases that impair N-glycosylation. Approximately 20% of patients do not survive beyond the age of 5 years old as a result of widespread organ dysfunction. Although most patients receive a CDG diagnosis based on abnormal glycosylation of transferrin, this test cannot provide a genetic diagnosis; indeed, many patients with abnormal transferrin do not have mutations in any known CDG genes. Here, we combined biochemical analysis with whole-exome sequencing (WES) to identify the genetic defect in an untyped CDG patient, and we found a 22 bp deletion and a missense mutation in DDOST, whose product is a component of the oligosaccharyltransferase complex that transfers the glycan chain from a lipid carrier to nascent proteins in the endoplasmic reticulum lumen. Biochemical analysis with three biomarkers revealed that N-glycosylation was decreased in the patient's fibroblasts. Complementation with wild-type-DDOST cDNA in patient fibroblasts restored glycosylation, indicating that the mutations were pathological. Our results highlight the power of combining WES and biochemical studies, including a glyco-complementation system, for identifying and confirming the defective gene in an untyped CDG patient. This approach will be very useful for uncovering other types of CDG as well.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / enzymology
  • Abnormalities, Multiple / genetics
  • Base Sequence
  • Biomarkers / metabolism
  • Child
  • Congenital Disorders of Glycosylation / enzymology
  • Congenital Disorders of Glycosylation / genetics*
  • Exome*
  • Fibroblasts / metabolism
  • Glycosylation
  • Hexosyltransferases / genetics*
  • Hexosyltransferases / metabolism
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Transferrin / metabolism


  • Biomarkers
  • Membrane Proteins
  • Transferrin
  • Hexosyltransferases
  • dolichyl-diphosphooligosaccharide - protein glycotransferase