Haploinsufficiency of ARFGEF1 is associated with developmental delay,intellectual disability,and epilepsy with variable expressivity |
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| Institution: | 1. Inserm UMR1231 team GAD, University of Burgundy and Franche-Comté, Dijon, France;2. Genetics Center, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France;3. Department of Neurology, Dijon Bourgogne University Hospital, Dijon, France;4. Institute for Advanced Biology, Centre de Recherche UGA, INSERM U1209, CNRS UMR 5309, Site Santé, Allée des Alpes, La Tronche, France;5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;6. Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait;7. Service de génétique médicale, CHU Nantes, Nantes, France;8. Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France;9. Unité INSERM U 1051, Département de Génétique Médicale, CHRU de Montpellier, Montpellier, France;10. University of Padova, Laboratorio Genetica Medica Bergamo, Bergamo, Italy;11. Functional Unit of Innovative Diagnosis for Rare Diseases, Dijon Bourgogne University Hospital, Dijon, France;12. Medical Genetics Department, Belfast City Hospital, Manchester, UK;13. Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK;14. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK;15. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA;16. Texas Children’s Hospital, Houston, TX, USA;17. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;18. College of Medicine, University of Baghdad, Baghdad, Iraq;19. Children Welfare Teaching Hospital, Baghdad, Iraq;20. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;21. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia;22. Divisions of Newborn Medicine and Genetics & Genomics, Manton Center for Orphan Disease Research, Boston, MA, USA;23. Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;24. Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;25. The Manton Center for Orphan Disease Research, Division of Genetics & Genomics; Boston Children’s Hospital, Boston, MA, USA;26. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;27. Centre de Référence des Malformations et Maladies Congénitales du Cervelet, et Département de Génétique, AP-HP.Sorbonne Université, Hôpital Trousseau, Paris, France;28. Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France;29. APHP, Service de Neuropédiatrie, Hôpital Armand Trousseau, UPMC Université, Paris, France;30. Centre de référence Déficiences Intellectuelles de Causes Rares, Dijon Bourgogne University Hospital, Dijon, France;31. Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Dijon Bourgogne University Hospital, Dijon, France;1. Inserm UMR1231 team GAD, University of Burgundy and Franche-Comté, Dijon, France;2. Genetics Center, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France;3. Department of Neurology, Dijon Bourgogne University Hospital, Dijon, France;4. Institute for Advanced Biology, Centre de Recherche UGA, INSERM U1209, CNRS UMR 5309, Site Santé, Allée des Alpes, La Tronche, France;5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;6. Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait;7. Service de génétique médicale, CHU Nantes, Nantes, France;8. Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France;9. Unité INSERM U 1051, Département de Génétique Médicale, CHRU de Montpellier, Montpellier, France;10. University of Padova, Laboratorio Genetica Medica Bergamo, Bergamo, Italy;11. Functional Unit of Innovative Diagnosis for Rare Diseases, Dijon Bourgogne University Hospital, Dijon, France;12. Medical Genetics Department, Belfast City Hospital, Manchester, UK;13. Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK;14. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK;15. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA;16. Texas Children’s Hospital, Houston, TX, USA;17. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;18. College of Medicine, University of Baghdad, Baghdad, Iraq;19. Children Welfare Teaching Hospital, Baghdad, Iraq;20. Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;21. Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia;22. Divisions of Newborn Medicine and Genetics & Genomics, Manton Center for Orphan Disease Research, Boston, MA, USA;23. Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;24. Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;25. The Manton Center for Orphan Disease Research, Division of Genetics & Genomics; Boston Children’s Hospital, Boston, MA, USA;26. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA;27. Centre de Référence des Malformations et Maladies Congénitales du Cervelet, et Département de Génétique, AP-HP.Sorbonne Université, Hôpital Trousseau, Paris, France;28. Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France;29. APHP, Service de Neuropédiatrie, Hôpital Armand Trousseau, UPMC Université, Paris, France;30. Centre de référence Déficiences Intellectuelles de Causes Rares, Dijon Bourgogne University Hospital, Dijon, France;31. Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Dijon Bourgogne University Hospital, Dijon, France |
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| Abstract: | PurposeADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.MethodsInternational data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.ResultsWe identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.ConclusionWe provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy. |
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