{"doi":"10.1093/clinchem/hvaf048","title":"Congenital Disorder of Glycosylation in a 40-Year-Old Male with Hypogammaglobulinemia","abstract":"A 40-year-old male presented with significant pan-hypogammaglobulinemia, gout with polyarticular pain, and type II diabetes mellitus with obesity. He was nondysmorphic, had dyslexia and a speech impediment, but did well in school without any developmental delay. His immune evaluation was significant for low IgG at 212 mg/dL (600–1600), IgA 17 mg/dL (80–300), and IgM 28 mg/dL (40–2500) despite normal circulating B lymphocyte counts and poor responses to polysaccharide vaccination. Clinically, he had a history of recurrent upper respiratory infections beginning in childhood, which improved in his 20s. His laboratory evaluation was consistent with common variable immune deficiency, but he was unable to tolerate either intravenous or subcutaneous immunoglobulin due to significant worsening of chronic migraines. He remains off IgG replacement and currently has no issues with infections. An immune genetic disease gene panel was obtained and showed 2 variants in MOGS (MIM #601336): 1. c.94_95insTCCG [p.(Gly32Valfs*9)] classified as pathogenic and 2. c.456C > G [p.(Asp152Glu)] classified as a variant of unknown significance. Neither parent was available for testing. Plasma carbohydrate-deficient transferrin and urine hexose 4 levels were normal. A plasma N-glycan analysis was performed, which showed increased Glc3Man7GlcNAc2. Fractionated N-glycan analysis showed increased Glc3Man7-8GlcNAc2 in immunopurified IgG, increased Glc3Man7GlcNAc2, and reduced hybrid glycans in the triple depleted fraction (with IgG, transferrin, and albumin removed), which supported a diagnosis of mannosyl-oligosaccharide glucosidase-congenital disorder of glycosylation (MOGS-CDG) (1). The N-glycan profile of transferrin was normal. Liquid chromatography-high-resolution accurate mass-mass spectrometry using an Orbitrap IQ-X Tribrid MS was performed to separate glucosylated glycans from isomers and isobars in plasma N-glycans. The separation of isobars Glc3Man9GlcNAc2 and Fuc1Neu5Ac2Gal2Man3GlcNAc4 (with delta m/z of 0.0198) was achieved by high-resolution accurate mass-mass spectrometry, and the isomers Man9GlcNAc2 and Glc3Man6GlcNAc2 were separated by a HILLIC column running 0.2 mL/min at 60°C, ramping from 34% to 100% mobile phase A (50 mM ammonium formate pH 4.4) over 32 mins and mobile phase B (100% acetonitrile) (2). IgG N-glycans purified from a known MOGS-CDG plasma were used to annotate 4 glucosylated glycans Glc3Man6-9GlcNAc2. All were found increased in the proband, confirming the diagnosis of MOGS-CDG (Fig. 1A-C).","journal":"Clinical Chemistry","year":2025,"id":569775,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9492,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":403797,"name":"Derek A. Wong","orcid":"0000-0002-7762-2276","position":1,"is_corresponding":false},{"id":692829,"name":"Wenyue Zhang","orcid":"0000-0001-8181-8282","position":2,"is_corresponding":false},{"id":238406,"name":"Caroline Y. Kuo","orcid":"0000-0002-9302-0187","position":3,"is_corresponding":false},{"id":273541,"name":"Miao He","orcid":"0000-0003-0731-6801","position":4,"is_corresponding":false},{"id":1474888,"name":"Idris J. Wazeerud‐Din","orcid":"0000-0002-7364-5761","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:57:03.510013Z","pmid":"40613798","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}