Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature |
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| Institution: | 1. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;2. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada;3. Oncode Institute and Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands;4. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, 00165 Rome, Italy;5. Division of Clinical Genetics, Department of Pediatrics, Columbia University, New York, NY;6. Service de Génétique Médicale et de Biologie de la Reproduction, Centre Hospitalier Regional Universitaire Brest, Brest, France;7. Centre de Génétique Humaine, CHU de Besançon, Université de Franche-Comté, Besançon, France;8. Greenwood Genetic Center, Greenwood, SC;9. Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy;10. Department of Medical Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands;11. Medical Genetics Unit, A.O.R.N. San Pio, Benevento, Italy;12. Laboratorio di Genetica Medica - ASST Papa Giovanni XXIII, Bergamo, Italy;13. Department of Medical Genetics, BC Children’s Hospital Research Institute, The University of British Columbia, Vancouver, British Columbia, Canada;14. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;15. Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada;16. Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan;17. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar;18. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program and Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA;19. The Rina Mor Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel;20. Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands;21. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan;22. The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petach-Tikva, Israel;23. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;24. Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon;25. Institut Jérôme Lejeune, Paris, France;26. Department of Medical Genetics, CHU Bordeaux, Bordeaux, France;27. Department of Pediatric Hematology and Oncology and Cellular and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Rome, Italy;28. Center for Rare Diseases and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;29. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany;30. Center of Functional Genomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany;31. Université de Brest, Inserm, EFS, UMR 1078, GGB, Brest, France;32. Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands;33. Clinical Genetics Unit, Department of Women and Children''s Health, University of Padova, Padova, Italy;34. Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA;35. Molecular Genetic Laboratory, Edith Wolfson Medical Center, Holon, Israel;36. Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA;37. Faculty of Medicine and Surgery, Catholic University of Sacred Heart, Rome, Italy |
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| Abstract: | PurposePathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.MethodsThrough international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature.ResultsWe recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism.ConclusionPathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood. |
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| Keywords: | Human Genetics KDM2B MDEMs Methylation signatures Neurodevelopmental disorders |
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