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Fetal glycosylation defect due to ALG3 and GOG5 variants detected via amniocentesis: complex glycosylation defect with embryonic lethal phenotype

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Author(s)

  • Alejandro Ferrer
  • Rodrigo Tzovenos Starosta
  • Wasantha Ranatunga
  • Dani Ungar
  • Tamas Kozicz
  • Eric Klee
  • Laura Rust
  • Myra Wick
  • Eva Morava

Department/unit(s)

Publication details

JournalMolecular genetics and metabolism
DateAccepted/In press - 2 Nov 2020
DateE-pub ahead of print - 7 Nov 2020
DatePublished (current) - Dec 2020
Issue number4
Volume131
Pages (from-to)424-429
Early online date7/11/20
Original languageEnglish

Abstract

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.

Bibliographical note

© 2020 Published by Elsevier Inc. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy.

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