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TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability
Authors:Silvia Radenkovic  Diego Martinelli  Yuebo Zhang  Graeme J Preston  Arianna Maiorana  Alessandra Terracciano  Maria Lisa Dentici  Elisa Pisaneschi  Antonio Novelli  Wasantha Ranatunga  Anna N Ligezka  Bart Ghesquière  David R Deyle  Tamas Kozicz  Filippo Pinto e Vairo  Peter Witters  Eva Morava
Institution:1. Department of Clinical Genomics, Mayo Clinic, Rochester, MN;2. Laboratory of Hepatology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium;3. Metabolomics Expertise Center, Center for Cancer Biology, VIB-KU Leuven, Leuven, Belgium;4. Metabolomics Expertise Center, Department of Oncology, KU Leuven, Leuven, Belgium;5. Division of Metabolism, Department of Pediatrics Specialties, Bambino Gesù Children’s Research Hospital, Rome, Italy;6. Medical Genetics Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy;7. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital IRCCS, Rome, Italy;8. Metabolic Center, University Hospitals Leuven, Leuven, Belgium;9. Department of Development and Regeneration, Faculty of Medicine, KU Leuven, Leuven, Belgium;10. Department of Medical Genetics, Medical School, University of Pécs, Pecs, Hungary;1. Genomics Policy Unit, University of South Wales, Pontypridd, United Kingdom;2. William F. Connell School of Nursing, Boston College, Chestnut Hill, MA;3. Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;4. School of Nursing, University of Northern British Columbia, Prince George, British Columbia, Canada;5. Ross and Carol Nese College of Nursing, The Pennsylvania State University, University Park, PA;6. Genetic Counselling, Genomics England, London, United Kingdom;1. Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;3. Faculty of Health Sciences, Ben Gurion University of the Negev, Be’er Sheva, Israel;4. Genetic Institute, Soroka University Medical Center, Be’er Sheva, Israel;5. Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;1. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy;2. Unit of Chronobiology, Division of Internal Medicine, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy;3. Institute for Applied Mathematics “Mauro Picone” National Research Council, Naples, Italy;4. Center for Human Genetics, University Hospital Leuven, Leuven, Belgium;5. Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy;6. Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich and University of Zurich, Zurich, Switzerland;7. Department of Clinical Genetics and Genomics, Turku University Hospital and University of Turku, Turku, Finland;8. Medical Genetics Unit, Meyer Children’s University Hospital, Florence, Italy;9. Medical Genetics Unit, University of Florence, Florence, Italy;10. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy;11. Department of Translational Medicine, University of Naples “Federico II”, Naples, Italy;12. Center for Medical Genetics and Department of Biomolecular Medicine, Ghent University Hospital, Ghent, Belgium;1. Institiute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY;2. Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NY;3. Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, NY;4. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, NY;5. Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, NY;6. Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY;1. Department of Medical Genetics, Reference Centre for Rare Diseases, Developmental Anomalies and Malformation Syndromes Sud-Est, Clermont-Ferrand University Hospital, Clermont-Ferrand, France;2. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada;3. Molecular Diagnostics Program and Verspeeten Clinical Genome Centre, London Health Sciences and Saint Joseph’s Healthcare, London, Ontario, Canada;4. Autoinflammatory and Rare Diseases Unit, Medical Genetic Department for Rare Diseases and Personalized Medicine, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;5. Greenwood Genetic Center, JC Self Research Institute of Human Genetics, Greenwood, SC;6. Medical Genetic Department for Rare Diseases and Personalized Medicine, Montpellier University Hospital, Montpellier, France;7. Clinical Genetics Department, Poitiers University Hospital, Poitiers, France;8. Clinical genetic department, Righospitalet, Copenhagen, Denmark;9. Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark;10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;11. Medical Genetics Department, Bretagne-Atlantique Hospital, Vannes, France;12. Department of Molecular Genetics and Genomics, Rennes University Hospital, Rennes, France;13. Univ Rennes, CNRS, IGDR, UMR 6290, Rennes, France;14. Department of Clinical Genetics, Reference Centre for Rare Diseases, CLAD Ouest, Rennes University Hospital, Rennes, France;15. Texas Children''s Hospital, Houston, TX;16. Department of Medical Genetics, Oslo University Hospitals and University of Oslo, Oslo, Norway;17. Departments of Neurosciences and Pediatrics, University of California San Diego, San Diego, CA;18. Division of Neurology, Rady Children’s Hospital, San Diego, CA;19. Rady Children’s Institute for Genomic Medicine, Rady Children’s Hospital, San Diego, CA;20. Medical Genetics Laboratory, ASST Papa Giovanni XXIII, Bergamo, Italy;21. Department of Medical Genetics, Women Mother Children Hospital, Hospices Civils de Lyon, Lyon, France;22. Department of Medical Genetics, Reference Center for Developmental Anomalies, CLAD Ouest, Rennes University Hospital, ERN ITHACA, CNRS UMR 6290, Genetics and Development Institute, Rennes University, Rennes, France;23. Functional Unit of Innovative Diagnosis for Rare Diseases, Dijon Bourgogne University Hospital, Dijon, France;24. Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy;25. Division of Pediatric and Adolescent Medicine, Oslo University Hospital, and University of Oslo, Oslo, Norway;26. Department of Neurology, University of Utah, Salt Lake City, UT;1. Department of Health Policy and Management, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC;2. Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;3. Department of Industrial & Systems Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL;4. Division of Pediatric Genetics & Metabolism, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC;5. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC;6. Department of Economics, College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC;7. Department of Genetics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
Abstract:PurposeTRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.MethodsExome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients’ blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.ResultsAll 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.ConclusionWe identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.
Keywords:Congenital disorder of glycosylation  Dysmorphic features  Intellectual disability  N-glycosylation  TRAPPC9 deficiency
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