De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy |
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| Affiliation: | 1. Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands;2. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA;3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;4. Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany;5. Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;6. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA;7. Lehrstuhl für Sozialpädiatrie, Technische Universität München, Munich, Germany;8. Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Martinsried, Germany;9. Department of Pediatrics, University of Virginia, Charlottesville, VA, USA;10. Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA;11. GeneDx, Gaithersburg, MD, USA;12. kbo-Kinderzentrum München, Munich, Germany;13. Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany;14. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany;15. Departments of Clinical Genomics and Neurology, Mayo Clinic, Rochester, MN, USA;16. Department of Neurology, Mayo Clinic, Rochester, MN, USA;17. Division of Clinical Genetics, Children’s Mercy Kansas City, University of Missouri Kansas City School of Medicine, Kansas city, MO, USA;18. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA;19. Ann & Robert H. Lurie Children’s Hospital, Epilepsy Center, Chicago, IL, USA;20. Division of Genetics and Genomics, Department of Medicine, Boston Children’s Hospital, Harvard Medical SchoolBoston, MA, USA;1. Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands;2. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA;3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA;4. Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany;5. Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany;6. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA;7. Lehrstuhl für Sozialpädiatrie, Technische Universität München, Munich, Germany;8. Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Martinsried, Germany;9. Department of Pediatrics, University of Virginia, Charlottesville, VA, USA;10. Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA;11. GeneDx, Gaithersburg, MD, USA;12. kbo-Kinderzentrum München, Munich, Germany;13. Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany;14. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany;15. Departments of Clinical Genomics and Neurology, Mayo Clinic, Rochester, MN, USA;16. Department of Neurology, Mayo Clinic, Rochester, MN, USA;17. Division of Clinical Genetics, Children’s Mercy Kansas City, University of Missouri Kansas City School of Medicine, Kansas city, MO, USA;18. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA;19. Ann & Robert H. Lurie Children’s Hospital, Epilepsy Center, Chicago, IL, USA;20. Division of Genetics and Genomics, Department of Medicine, Boston Children’s Hospital, Harvard Medical SchoolBoston, MA, USA |
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| Abstract: | PurposeThis study characterizes the clinical and genetic features of nine unrelated patients with de novo variants in the NR4A2 gene.MethodsVariants were identified and de novo origins were confirmed through trio exome sequencing in all but one patient. Targeted RNA sequencing was performed for one variant to confirm its splicing effect. Independent discoveries were shared through GeneMatcher.ResultsMissense and loss-of-function variants in NR4A2 were identified in patients from eight unrelated families. One patient carried a larger deletion including adjacent genes. The cases presented with developmental delay, hypotonia (six cases), and epilepsy (six cases). De novo status was confirmed for eight patients. One variant was demonstrated to affect splicing and result in expression of abnormal transcripts likely subject to nonsense-mediated decay.ConclusionOur study underscores the importance of NR4A2 as a disease gene for neurodevelopmental disorders and epilepsy. The identified variants are likely causative of the seizures and additional developmental phenotypes in these patients. |
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