Alejandro Ferrer1, Rodrigo Tzovenos Starosta2, Wasantha Ranatunga3, Dani Ungar4, Tamas Kozicz1, Eric Klee1, Laura M Rust5, Myra Wick5, Eva Morava6. 1. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. 2. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA; Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. 3. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. 4. Department of Biology, University of York, York, UK. 5. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA; Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN, USA. 6. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Electronic address: morava-kozicz.eva@mayo.edu.
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.
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.
Authors: Anna N Ligezka; Silvia Radenkovic; Mayank Saraswat; Kishore Garapati; Wasantha Ranatunga; Wirginia Krzysciak; Hitoshi Yanaihara; Graeme Preston; William Brucker; Renee M McGovern; Joel M Reid; David Cassiman; Karthik Muthusamy; Christin Johnsen; Saadet Mercimek-Andrews; Austin Larson; Christina Lam; Andrew C Edmondson; Bart Ghesquière; Peter Witters; Kimiyo Raymond; Devin Oglesbee; Akhilesh Pandey; Ethan O Perlstein; Tamas Kozicz; Eva Morava Journal: Ann Neurol Date: 2021-10-26 Impact factor: 10.422
Authors: Martina Farolfi; Anna Cechova; Nina Ondruskova; Jana Zidkova; Bohdan Kousal; Hana Hansikova; Tomas Honzik; Petra Liskova Journal: BMC Ophthalmol Date: 2021-06-05 Impact factor: 2.209