Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (p < 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (p < 0.0001). Nine out of 33 patients died (p = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.

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

Children's Clinic Tartu University Hospital Tartu Estonia

Department of Clinical Genetics Genetics and Personalized Medicine Clinic Tartu University Hospital Tartu Estonia

Department of Development and Regeneration KU Leuven Leuven Belgium

Department of Human Genetics and Neurology Translational Metabolic Laboratory Donders Center for Brain Cognition and Behavior Radboud University Medical Center Nijmegen The Netherlands

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

Department of Internal Medicine Radboud University Medical Centre Nijmegen The Netherlands

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

Department of Paediatrics and Metabolic Center University Hospitals Leuven Leuven Belgium

Department of Pediatrics Milano Bicocca University San Gerardo Hospital Monza Italy

Division of Metabolism Bambino Gesù Children's Research Hospital Rome Italy

Institute of Clinical Medicine University of Tartu Tartu Estonia

Metabolic Unit Great Ormond Street Hospital and Institute of Child Health University College London NHS Trust London UK

Neurology Department Hospital Sant Joan de Déu U 703 Centre for Biomedical Research on Rare Diseases Instituto de Salud Carlos 3 Barcelona Spain

Oasi Research Institute IRCCS Troina Italy

One Day Clinic The Institute of Mother and Child Warsaw Poland

Tallinn Children's Hospital Tallinn Estonia

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