BACKGROUND AND AIMS: Congenital disorders of glycosylation (CDG) are rare diseases caused by defects in protein glycosylation. We present an infant with multisystemic clinical involvement, diagnosed with COG6-CDG. METHODS: Serum and transferrin-linked N-glycans, as well as serum and apolipoprotein CIII-linked O-glycans, were analyzed by MALDI mass spectrometry. Mutation analysis was performed by next-generation sequencing. Functional studies assessed COG6 subunit expression, cooperating subunits, and retrograde transport. GlycoWorks RapiFluor-MS-based N-glycan labeling with HPLC-FLD and ESI-Orbitrap mass spectrometry enabled further comprehensive glycoprofile analysis. RESULTS: Aberrant glycosylation typical of combined N- and O-glycosylation defects was detected. Mutation analysis identified a novel homozygous variant in the COG6 gene: c.906_907delinsA, p.(His302GlnfsTer4), introducing a premature stop codon and producing a truncated protein of only 304 amino acids. The diagnosis of COG6-CDG was confirmed by the complete absence of the COG6 subunit, impairment of two other cooperating subunits, and delayed retrograde transport. Independent glycoprofile analyses by HPLC-FLD and ESI-Orbitrap revealed a set of potential glycobiomarkers of COG6-CDG, including underprocessed N-glycans Hex3-5HexNAc2, Hex3-5HexNAc3, Hex3-4HexNAc4, and Hex4HexNAc3-4NeuAc1. CONCLUSION: This study describes a novel COG6 variant leading to complete loss of protein function and major glycosylation abnormalities. Multiomics analysis provided deeper insights into the molecular mechanisms of this rare disease and the function of the COG6 gene and demonstrated how the mutation results in significant alterations in the patient's (glyco)phenotype.

Ambulance of Medical Genetics Children's Faculty Hospital and Slovak Health University Banská Bystrica Slovakia

Ambulance of Medical Genetics Unilabs Slovakia Banská Bystrica Slovakia

Ambulance of Medical Genetics Unilabs Slovakia Košice Slovakia

Department of Clinical Neurosciences Center of Clinical and Preclinical Research MEDIPARK Pavol Jozef Šafárik University Košice Slovakia

Department of Glycobiology Institute of Chemistry Slovak Academy of Sciences Bratislava Slovakia

Department of Laboratory Medicine National Institute of Children's Diseases Bratislava Slovakia

Department of Medical Genetics F D Roosevelt University Hospital With Policlinic Banská Bystrica Banská Bystrica Slovakia

Department of Neurology Faculty of Medicine Pavol Jozef Šafárik University Košice Slovakia

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Institute of Molecular Biology Slovak Academy of Sciences Bratislava Slovakia

Laboratory of Medical Genetics Unilabs Slovakia Bratislava Slovakia

Pediatric Neurology Ambulance Children's Faculty Hospital With Clinic Banská Bystrica Banská Bystrica Slovakia

The Ambulance of Pediatric Endocrinology and Diabetology and Metabolic and Nutritional Disorders Children's Faculty Hospital With Clinic Banská Bystrica Banská Bystrica Slovakia

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