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
Data availability statement
Data are available on reasonable request.
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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.
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