CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature |
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| Authors: | Flavien Rouxel Raissa Relator Jennifer Kerkhof Haley McConkey Michael Levy Patricia Dias Mouna Barat-Houari Nathalie Bednarek Odile Boute Nicolas Chatron Florian Cherik Andrée Delahaye-Duriez Martine Doco-Fenzy Laurence Faivre Lucas W. Gauthier Delphine Heron Michael S. Hildebrand Gaëtan Lesca David Genevieve |
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| Affiliation: | 1. Génétique clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU Montpellier, Montpellier University, Centre de Référence Anomalies du Développement SOOR, INSERM U1183, ERN ITHACA, Montpellier, France;2. The Archie & Irene Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada;3. Genetics Department, Hospital Center of Lisbon North, ERN ITHACA, Lisbon, Portugal;4. Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Génétique des Maladies Rares et Auto-Inflammatoires, CHU Montpellier, Université de Montpellier, Montpellier, France;5. Genetics Department, CHU Reims, Medical school IFR53, EA3801, Reims, France;6. Genetics Department, Guy Fontaine Medical Center, CLAD Nord de France, Jeanne de Flandre Hospital, CHRU Lille, Lille, France;7. Genetics Department, Lyon University Hospital, and Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Claude Bernard Lyon 1 University, Lyon, France;8. Genetics Department, CHU Clermont-Ferrand, Clermont-Ferrand, France;9. Department of Histology Embryology and Cytogenetics, Jean Verdier Hospital; Paris 13 University, Sorbonne Paris Cité, UFR SMBH Bobigny; PROTECT, INSERM, Paris Diderot University, Paris, France;10. Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France;11. Genetics of Developmental Disorders, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Dijon, France;12. Genetics Department, University Hospital Pitié-Salpétrière, Paris, France;13. Epilepsy Research Center, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia;14. Murdoch Children''s Research Institute, Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, Victoria, Australia;15. Chromosomic genetic laboratory, CH Général, Chambéry, France;16. Department of Pediatrics, Emma Children''s Hospital, Amsterdam UMC, University of Amsterdam, ERN ITHACA, Amsterdam, Netherlands;17. Department of Audiology and Speech Pathology, Melbourne School of Health Sciences, The University of Melbourne, Parkville, Victoria, Australia;18. Department of Clinical Genetics, CLAD Ouest, CHU de Rennes, Hôpital Sud, Rennes, France;19. Genetics Department, Referral Centre for Developmental Abnormalities, Lyon University Hospital Lyon, France;20. INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre, GENDEV Team, Claude Bernard Lyon 1 University, Lyon, France;21. Functional Unit 6254 Innovation in Genomic Diagnosis of Rare Diseases, CHU Dijon Bourgogne, Dijon, France;22. Genetics Department, CHU de Nantes, Nantes, France;23. Genetics Department, CHU de Poitiers, Poitiers University Hospital, Poitiers, France;24. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada;1. Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milan, Italy;2. Pediatric Radiology and Neuroradiology Department, Vittore Buzzi Children’s Hospital, Milan, Italy;3. COALA (Center for diagnosis and treatment of leukodystrophies), Vittore Buzzi Children''s Hospital, Milan, Italy;4. Child Neuropsychiatry Unit, UONPIA ASST Rhodense, Milan, Italy;5. Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, University of Milan, Milan, Italy;6. Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam, University of Amsterdam, Amsterdam, The Netherlands;7. Molecular Genetics Section, Medical Genetics Laboratory, Papa Giovanni XXIII Hospital, Bergamo, Italy;8. Child Neurology Unit, Vittore Buzzi Children''s Hospital, Milan, Italy;1. Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;2. MRC Unit for Genomic and Precision Medicine, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;3. Department of Biochemistry and Medical Microbiology, School of Medicine, University of Namibia, Windhoek, Namibia;4. Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;5. Division of Human Genetics, Department of Pathology, Colorectal Cancer Research Group, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa;1. School of Women’s and Children’s Health, University of New South Wales, Randwick, New South Wales, Australia;2. Centre for Clinical Genetics, Sydney Children’s Hospital, Randwick, New South Wales, Australia;3. Sydney Health Ethics, Sydney School of Public Health, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia;4. Victorian Clinical Genetics Services, Parkville, Victoria, Australia;5. Murdoch Children’s Research Institute, Parkville, Victoria, Australia;6. UWA Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia;7. Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia;8. NSW Health Pathology East Genomics Laboratory, Randwick, New South Wales, Australia;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. The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA;2. Department of Biostatistics, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;3. Department of Health Policy, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;4. Institute for Public Health Genetics, University of Washington School of Public Health, Seattle, WA;5. Department of Health Policy & Behavioral Sciences, School of Public Health, Georgia State University, Atlanta, GA;6. Genomic Medicine Institute, Geisinger, Danville, PA;7. Department of Population Health Sciences, Geisinger, Danville, PA;8. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN;1. Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium;2. StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium;3. Ann & Robert H. Lurie Children’s Hospital, Chicago, IL;4. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, The Johns Hopkins University, Baltimore, MD;5. Howard Hughes Medical Institute, Baltimore, MD;6. Department of Pediatrics, Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, SC;7. Departments of Pediatrics and Genetics & Genomic Sciences, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY;8. Division of Cardiology, Children''s Hospital of Philadelphia, Philadelphia, PA;9. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;10. Departments of Pediatrics and Internal Medicine, University of Utah and Intermountain Healthcare, Salt Lake City, UT;11. Department of Pediatrics, Duke University School of Medicine, Durham, NC;12. Children’s Hospital of New York, New York City, NY;13. Department of Pediatrics, Division of Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;14. Division of Cardiology, Department of Pediatrics, Baylor College of Medicine and Texas Children''s Hospital, Houston, TX;15. Department of Pediatrics, Seattle Children’s Hospital, Seattle, WA;16. Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium;17. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN;18. Department of Cardiology, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA;19. Department of Paediatrics, Stanford University, Palo Alto, CA;20. Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH;21. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO;22. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands |
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| Abstract: | PurposeRare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation.MethodsWe obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine–based classifier distinguishing CDK13-RD and non–CDK13-RD samples.ResultsWe reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance.ConclusionWe describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder. |
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| Keywords: | CDK13 CHDFIDD Clinical Epigenetic Signature |
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