Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation

Shino Shimada; Bobby G Ng; Amy L White; Kim K Nickander; Coleman Turgeon; Kristen L Liedtke; Christina T Lam; Esperanza Font-Montgomery; Charles M Lourenco; Miao He; Dawn S Peck; Luis A Umana; Crescenda L Uhles; Devon Haynes; Patricia G Wheeler; Michael J Bamshad; Deborah A Nickerson; Tom Cushing; Ryan Gates; Natalia Gomez-Ospina; Heather M Byers; UW Center for Mendelian Genomics; Fernanda B Scalco; Noelia N Martinez; Rani Sachdev; Lacey Smith; Annapurna Poduri; Stephen Malone; Rebekah V Harris; Ingrid E Scheffer; Sergio D Rosenzweig; David R Adams; William A Gahl; May Christine V Malicdan; Kimiyo M Raymond; Hudson H Freeze; Lynne A Wolfe

doi:10.1136/jmedgenet-2021-108177

Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation

J Med Genet. 2022 Jul 5:jmedgenet-2021-108177. doi: 10.1136/jmedgenet-2021-108177. Online ahead of print.

Authors

Shino Shimada^#^{1

2}, Bobby G Ng^#³, Amy L White^#⁴, Kim K Nickander⁴, Coleman Turgeon⁴, Kristen L Liedtke⁴, Christina T Lam^{5

6}, Esperanza Font-Montgomery⁷, Charles M Lourenco^{8

9}, Miao He¹⁰, Dawn S Peck⁴, Luis A Umana¹¹, Crescenda L Uhles¹², Devon Haynes¹³, Patricia G Wheeler¹³, Michael J Bamshad^{6

14}, Deborah A Nickerson¹⁵, Tom Cushing¹⁶, Ryan Gates¹⁷, Natalia Gomez-Ospina¹⁷, Heather M Byers¹⁷; UW Center for Mendelian Genomics; Fernanda B Scalco¹⁸, Noelia N Martinez¹⁹, Rani Sachdev^{19

20}, Lacey Smith²¹, Annapurna Poduri²¹, Stephen Malone²², Rebekah V Harris²³, Ingrid E Scheffer^{23

24}, Sergio D Rosenzweig²⁵, David R Adams^{26

2}, William A Gahl^{26

2}, May Christine V Malicdan^#^{26

2}, Kimiyo M Raymond^#⁴, Hudson H Freeze^#³, Lynne A Wolfe^#^{26

2}

Collaborators

UW Center for Mendelian Genomics:
Michael J Bamshad, Deborah A Nickerson, Peter Anderson, Tamara J Bacus, Elizabeth E Blue, Katherine Brower, Kati J Buckingham, Jessica X Chong, Colleen P Davis, Chayna J Davis, Christian D Frazar, Katherine Gomeztagle-Burgess, William W Gordon, Martha Horike-Pyne, Jameson R Hurless, Gail P Jarvik, Eric Johanson, J Thomas Kolar, Colby T Marvin, Sean McGee, Daniel J McGoldrick, Betselote Mekonnen, Patrick M Nielsen, Karynne Patterson, Aparna Radhakrishnan, Matthew A Richardson, Gwendolin T Roote, Erica L Ryke, Kathryn M Shively, Joshua D Smith, Monica Tackett, Jeffrey M Weiss, Marsha M Wheeler, Qian Yi, Xiaohong Zhang

Affiliations

¹ Medical Genetic Branch, National Human Genome Research Institute, Bethesda, Maryland, USA s-shimada@juntendo.ac.jp.
² Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
³ Human Genetics Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA.
⁴ Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
⁶ Department of Pediatrics, University of Washington, Seattle, Washington, USA.
⁷ University Hospital Medical Genetics Clinic, University of Missouri, Columbia, Missouri, USA.
⁸ Department of Medical Genetics, School of Medicine, Neurogenetics Unit, University, Sao Paulo, Sao Paulo, Brazil.
⁹ Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, Brazil.
¹⁰ Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹¹ Division of Genetics and Metabolism, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹² Department of Genetics, Children's Medical Center Dallas, Dallas, Texas, USA.
¹³ Division of Genetics, Arnold Palmer Hospital for Children, Orlando, Florida, USA.
¹⁴ Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
¹⁵ Professor of Genome Sciences and Bioengineering, University of Washington, Seattle, Washington, USA.
¹⁶ Division of Pediatric Genetics, Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
¹⁷ Division of Medical Genetics, Stanford University, Stanford, California, USA.
¹⁸ Laboratório de Erros Inatos do Metabolismo/LABEIM, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
¹⁹ Center for Clinical Genetics, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia.
²⁰ School of Women's & Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
²¹ Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
²² Department of Neurosciences, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
²³ Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
²⁴ Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
²⁵ Department of Laboratory Medicine, Clinical Center, and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
²⁶ Medical Genetic Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.

^# Contributed equally.

Abstract

Purpose: To summarise the clinical, molecular and biochemical phenotype of mannosyl-oligosaccharide glucosidase-related congenital disorders of glycosylation (MOGS-CDG), which presents with variable clinical manifestations, and to analyse which clinical biochemical assay consistently supports diagnosis in individuals with bi-allelic variants in MOGS.

Methods: Phenotypic characterisation was performed through an international and multicentre collaboration. Genetic testing was done by exome sequencing and targeted arrays. Biochemical assays on serum and urine were performed to delineate the biochemical signature of MOGS-CDG.

Results: Clinical phenotyping revealed heterogeneity in MOGS-CDG, including neurological, immunological and skeletal phenotypes. Bi-allelic variants in MOGS were identified in 12 individuals from 11 families. The severity in each organ system was variable, without definite genotype correlation. Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal.

Conclusion: The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity. Molecular analysis, combined with biochemical testing, is important for diagnosis. In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.

Keywords: central nervous system diseases; diagnosis; glycomics; human genetics; sequence analysis, DNA.

Abstract

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