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Phenotypes
Original research
Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation
  1. Shino Shimada1,2,
  2. Bobby G Ng3,
  3. Amy L White4,
  4. Kim K Nickander4,
  5. Coleman Turgeon4,
  6. Kristen L Liedtke4,
  7. Christina T Lam5,6,
  8. Esperanza Font-Montgomery7,
  9. Charles M Lourenco8,9,
  10. Miao He10,
  11. Dawn S Peck4,
  12. Luis A Umana11,
  13. Crescenda L Uhles12,
  14. Devon Haynes13,
  15. Patricia G Wheeler13,
  16. Michael J Bamshad6,14,
  17. Deborah A Nickerson15,
  18. Tom Cushing16,
  19. Ryan Gates17,
  20. Natalia Gomez-Ospina17,
  21. Heather M Byers17,
  22. UW Center for Mendelian Genomics,
  23. Fernanda B Scalco18,
  24. Noelia N Martinez19,
  25. Rani Sachdev19,20,
  26. Lacey Smith21,
  27. Annapurna Poduri21,
  28. Stephen Malone22,
  29. Rebekah V Harris23,
  30. Ingrid E Scheffer23,24,
  31. Sergio D Rosenzweig25,
  32. David R Adams1,2,
  33. William A Gahl1,2,
  34. May Christine V Malicdan1,2,
  35. Kimiyo M Raymond4,
  36. Hudson H Freeze3,
  37. Lynne A Wolfe1,2
    1. 1 Medical Genetic Branch, National Human Genome Research Institute, Bethesda, Maryland, USA
    2. 2 Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
    3. 3 Human Genetics Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, California, USA
    4. 4 Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
    5. 5 Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, USA
    6. 6 Department of Pediatrics, University of Washington, Seattle, Washington, USA
    7. 7 University Hospital Medical Genetics Clinic, University of Missouri, Columbia, Missouri, USA
    8. 8 Department of Medical Genetics, School of Medicine, Neurogenetics Unit, University, Sao Paulo, Sao Paulo, Brazil
    9. 9 Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, Brazil
    10. 10 Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    11. 11 Division of Genetics and Metabolism, Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
    12. 12 Department of Genetics, Children’s Medical Center Dallas, Dallas, Texas, USA
    13. 13 Division of Genetics, Arnold Palmer Hospital for Children, Orlando, Florida, USA
    14. 14 Department of Genome Sciences, University of Washington, Seattle, Washington, USA
    15. 15 Professor of Genome Sciences and Bioengineering, University of Washington, Seattle, Washington, USA
    16. 16 Division of Pediatric Genetics, Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
    17. 17 Division of Medical Genetics, Stanford University, Stanford, California, USA
    18. 18 Laboratório de Erros Inatos do Metabolismo/LABEIM, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
    19. 19 Center for Clinical Genetics, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia
    20. 20 School of Women’s & Children’s Health, University of New South Wales, Sydney, New South Wales, Australia
    21. 21 Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    22. 22 Department of Neurosciences, Queensland Children's Hospital, South Brisbane, Queensland, Australia
    23. 23 Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
    24. 24 Department of Paediatrics, The University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia
    25. 25 Department of Laboratory Medicine, Clinical Center, and Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
    1. Correspondence to Dr Shino Shimada, Medical Genetic Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA; s-shimada{at}juntendo.ac.jp

    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.

    • human genetics
    • sequence analysis, DNA
    • central nervous system diseases
    • diagnosis
    • glycomics

    Data availability statement

    Data are available on reasonable request.

    https://doi.org/10.1136/jmedgenet-2021-108177

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      Data availability statement

      Data are available on reasonable request.

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      Footnotes

      • SS, BGN and ALW are joint first authors.

      • MCVM, KMR, HHF and LAW are joint senior authors.

      • SS, BGN and ALW contributed equally.

      • MCVM, KMR, HHF and LAW contributed equally.

      • 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 and Xiaohong Zhang.

      • Contributors Clinical consult; summary of clinical data and interpretation: BGN, ALW, CTL, EF-M, CML, DSP, LAU, CLU, DH, PGW, TC, RG, NG-O, HB, NNM, RS, LS, AP, SM, RH, IS, SDR, DRA, LW, WAG, SS, HHF. Biochemical data analysis and interpretation: KKN, CT, KLL, MH, FSS, BGN, ALW, KMR, HHF. Funding acquisition: WAG, HHF, KMR. Acquisition of genetic data and its interpretation: UW-CMG, BGN, MJB, DN, SS, MCVM. Project conceptualisation: MCVM, SS, LW, KMR, HHF. Writing an original draft, figures and extensive revision: SS, ALW, HHF, MCVM. Supervision: MCVM, LW, KMR, HHF. All authors contributed to the writing and approved the final version of the manuscript. MCVM and WAG are the guarantors for the overall content of this study.

      • Funding This research was supported by the Intramural Research Programme of the National Human Genome Research Institute and the Common Fund of the NIH Office of the Director. The Freeze Lab was supported by The Rocket Fund, and NIH R01DK99551. SS was partly supported by the JSPS Research fellowship for Japanese Biomedical and Behaviour Research. RK, MH and HHF are partially supported by the NINDS/NCATS Frontiers in Congenital Disorders of Glycosylation Grant (1U54NS115198-01). IS is supported by the National Health and Medical Research Council of Australia. University of Washington Centre for Mendelian Genomics (UW-CMG) was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.