Fetal glycosylation defect due to ALG3 and COG5 variants detected via amniocentesis: Complex glycosylation defect with embryonic lethal phenotype

Mol Genet Metab. 2020 Dec;131(4):424-429. doi: 10.1016/j.ymgme.2020.11.003. Epub 2020 Nov 7.


Introduction: Congenital disorders of glycosylation (CDG) are inborn errors of glycan metabolism with high clinical variability. Only a few antenatal cases have been described with CDG. Due to a lack of reliable biomarker, prenatal CDG diagnostics relies primarily on molecular studies. In the presence of variants of uncertain significance prenatal glycosylation studies are very challenging.

Case report: A consanguineous couple had a history of second-trimester fetal demise with tetralogy of Fallot and skeletal dysplasia. In the consecutive pregnancy, the second trimester ultrasonography showed skeletal dysplasia, vermian hypoplasia, congenital heart defects, omphalocele and dysmorphic features. Prenatal chromosomal microarray revealed a large region of loss of heterozygosity. Demise occurred at 30 weeks. Fetal whole exome sequencing showed a novel homozygous likely pathogenic variant in ALG3 and a variant of uncertain significance in COG5.

Methods: Western blot was used to quantify ALG3, COG5, COG6, and the glycosylation markers ICAM-1 and LAMP2. RT-qPCR was used for ALG3 and COG5 expression in cultured amniocytes and compared to age matched controls.

Results: ALG3 and COG5 mRNA levels were normal. ICAM-1, LAMP2, ALG3 and COG5 levels were decreased in cultured amniocytes, suggesting the possible involvement of both genes in the complex phenotype.

Conclusion: This is the first case of successful use of glycosylated biomarkers in amniocytes, providing further options of functional antenatal testing in CDG.

Keywords: Congenital disorders of glycosylation; Fetal demise; Multi-Omics; Osteochondrodysplasia; Whole-exome sequencing.

Publication types

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

MeSH terms

  • Aborted Fetus / pathology
  • Abortion, Spontaneous / genetics
  • Adaptor Proteins, Vesicular Transport / genetics*
  • Amniocentesis
  • Congenital Disorders of Glycosylation / diagnosis
  • Congenital Disorders of Glycosylation / genetics*
  • Congenital Disorders of Glycosylation / pathology
  • Female
  • Glycosylation*
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Mannosyltransferases / genetics*
  • Mutation / genetics
  • Phenotype
  • Pregnancy


  • Adaptor Proteins, Vesicular Transport
  • COG5 protein, human
  • ICAM1 protein, human
  • LAMP2 protein, human
  • Lysosomal-Associated Membrane Protein 2
  • Intercellular Adhesion Molecule-1
  • ALG3 protein, human
  • Mannosyltransferases