We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration: NCT03173300.

Biochemistry and Genetics Department Bichat Claude Bernard Hospital AP HP University of Paris and Inserm U1149 Paris France

Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington USA

Centro de Genética Médica Centro Hospitalar Universitário de Santo António Porto Portugal

Child Neuropsychiatry Unit Department of Clinical and Experimental Medicine University of Catania Catania Italy

Children's Clinic Tartu University Hospital N Lunini Street 6 Tartu Estonia

Department of Clinical Genomics Mayo Clinic Rochester Minnesota USA

Department of Development and Regeneration Faculty of Medicine KU Leuven Leuven Belgium

Department of Genetics and Genomics Sciences Icahn School of Medicine at Mount Sinai New York City New York USA

Department of Genetics and Personalized Medicine Institute of Clinical Medicine University of Tartu L Puusepa Street 2 Tartu Estonia

Department of Inborn Errors of Metabolism and Paediatrics The Institute of Mother and Child Warsaw Poland

Department of Internal Medicine Radboud University Medical Centre Nijmegen Netherlands

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA

Department of Paediatrics Metabolic Disease Center University Hospitals Leuven Leuven Belgium

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

Departments of Neurology and Pediatric and Adolescent Medicine Mayo Clinic Rochester Minnesota USA

Division of Genetic Medicine Department of Pediatrics University of Washington School of Medicine Seattle Washington USA

Division of Human Genetics Department of Pediatrics Children's Hospital of Philadelphia Pennsylvania USA

Genetics and Personalized Medicine Clinic Tartu University Hospital L Puusepa Street 2 Tartu Estonia

Glycomine Inc San Francisco California USA

Pediatric Neurology Department and Clinical Biochemistry and Genetics Units Hospital Sant Joan de Déu Institut de Recerca Sant Joan de Déu Barcelona Spain

Reference Center for Inborn Errors of Metabolism Necker Hospital APHP University of Paris Inserm UMR_S1163 INEM and Institut Imagine Filière G2M MetabERN Paris France

Research Unit of Rare Diseases and Neurodevelopmental Disorders Oasi Research Institute IRCCS Troina Italy

U 703 Centre for Biomedical Research on Rare Diseases Instituto de Salud Carlos 3 Barcelona Spain

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