首页 | 本学科首页   官方微博 | 高级检索  
     


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
Affiliation: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
本文献已被 ScienceDirect 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号