[en] Rare genetic variants in ARID2 are responsible for a recently described neurodevelopmental condition called ARID2-related disorder (ARID2-RD). ARID2 belongs to PBAF, a unit of the SWI/SNF complex, which is a chromatin remodeling complex. This work aims to further delineate the phenotypic spectrum of ARID2-RD, providing clinicians with additional data for better care and aid in the future diagnosis of this condition. We obtained the genotypes and phenotypes of 27 previously unreported individuals with ARID2-RD and compared this series with findings in the literature. We also assessed peripheral blood DNA methylation profiles in individuals with ARID2-RD compared to episignatures of controls, unresolved cases, and other neurodevelopmental disorders. The main clinical features of ARID2-RD are developmental delay, speech disorders, intellectual disability (ID), behavior problems, short stature, and various dysmorphic and ectodermal features. Genome-wide differential methylation analysis revealed a global hypermethylated profile in ARID2-RD that could aid in reclassifying variants of uncertain significance. Our study doubles the number of reported individuals with ARID2 pathogenic variants to 53. It confirms loss-of-function as a pathomechanism and shows the absence of a clear genotype-phenotype correlation. We provide evidence for a unique DNA methylation episignature for ARID2-RD and further delineate the ARID2-associated phenotype.
Disciplines :
Genetics & genetic processes
Author, co-author :
Houdayer, Clara ; Service de Génétique Médicale, CHU d'Angers, Angers, France. clara.houdayer@chu-angers.fr ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France. clara.houdayer@chu-angers.fr
Rooney, Kathleen ; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada ; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
van der Laan, Liselot ; Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
Bris, Céline; Service de Génétique Médicale, CHU d'Angers, Angers, France ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France
Alders, Mariëlle; Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
Bahr, Angela; Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Switzerland
Barcia, Giulia ; Université Paris Cité, Service de Médecine Génomique des Maladies Rares, INSERM UMR 1163, Institut Imagine, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
Battault, Clarisse; Service de Génétique Médicale, CHU d'Angers, Angers, France
Begemann, Anais ; Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Switzerland
Bonneau, Dominique; Service de Génétique Médicale, CHU d'Angers, Angers, France ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France
Bonnevalle, Antoine; Normandy University, UNIROUEN, INSERM U1245 and University Hospital of Rouen, Department of Genetics and Reference Centre for Developmental Disorders, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
Boughalem, Aicha ; Laboratoire Cerba, Saint-Ouen-l'Aumone, France
Bourges, Alice; Service de Génétique Médicale, CHU d'Angers, Angers, France
Bournez, Marie ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Bruel, Ange-Line ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Buhas, Daniela; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Center, Montreal, QC, Canada ; Department of Human Genetics, McGill University, Montreal, QC, Canada
Carallis, Floriane; Laboratoire Multisites SeqOIA, Paris, France
Cogné, Benjamin ; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France ; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000, Nantes, France
Cormier-Daire, Valérie ; Université Paris Cité, Service de Médecine Génomique des Maladies Rares, INSERM UMR 1163, Institut Imagine, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
Delanne, Julian; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Demaret, Tanguy ; Université de Liège - ULiège ; Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium
Denommé-Pichon, Anne-Sophie ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Désir, Julie; Centre de Génétique Humaine, Institut de Pathologie et Génétique, Gosselies, Belgium
Dubourg, Christèle ; Service de Génétique Médicale, Centre Labellisé Anomalies du Développement de l'Ouest, CHU de Rennes, Rennes, France
Fradin, Mélanie ; Service de Génétique Médicale, Centre Labellisé Anomalies du Développement de l'Ouest, CHU de Rennes, Rennes, France
Geneviève, David ; Montpellier University, Inserm, U1183, Montpellier, France ; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
Goel, Himanshu; Hunter Genetics, Waratah, NSW, Australia
Goldenberg, Alice; Normandy University, UNIROUEN, INSERM U1245 and University Hospital of Rouen, Department of Genetics and Reference Centre for Developmental Disorders, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
Gripp, Karen W ; Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA
Guichet, Agnès; Service de Génétique Médicale, CHU d'Angers, Angers, France ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France
Guimier, Anne; Université Paris Cité, Service de Médecine Génomique des Maladies Rares, INSERM UMR 1163, Institut Imagine, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
JACQUINET, Adeline ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Keren, Boris; UF de Génétique Clinique et Centre de Référence Maladies Rares des Anomalies du Développement et Syndromes Malformatifs, ERN ITHACA, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France
Legoff, Louis ; Service de Génétique Médicale, CHU d'Angers, Angers, France ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France
Levy, Michael A; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
McConkey, Haley; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
Mendelsohn, Bryce A ; Department of Medical Genetics, Kaiser Oakland Medical Center, Oakland, CA, USA
Mignot, Cyril; APHP Sorbonne Université, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France
Milon, Vincent; Service de Génétique Médicale, CHU d'Angers, Angers, France
Nizon, Mathilde ; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France ; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000, Nantes, France
Oneda, Beatrice; Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Switzerland
Pasquier, Laurent ; Service de Génétique Médicale, Centre Labellisé Anomalies du Développement de l'Ouest, CHU de Rennes, Rennes, France
Patat, Olivier; Department of Genetics, University Hospital of Toulouse, Toulouse, France
Philippe, Christophe ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Procaccio, Vincent; Service de Génétique Médicale, CHU d'Angers, Angers, France ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France
Procopio, Rebecca; Division of Medical Genetics, Nemours/A.I. DuPont Hospital for Children, Wilmington, DE, USA
Prouteau, Clément; Service de Génétique Médicale, CHU d'Angers, Angers, France
Rambaud, Thomas; Laboratoire Multisites SeqOIA, Paris, France
Rauch, Anita ; Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Switzerland
Relator, Raissa; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada
Rondeau, Sophie; Université Paris Cité, Service de Médecine Génomique des Maladies Rares, INSERM UMR 1163, Institut Imagine, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
Santen, Gijs W E ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Schleit, Jennifer; Blueprint Genetics, Quest Diagnostics Company, 2505 3rd Ave, Suite 204, Seattle, WA, 98121, USA
Sorlin, Arthur ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Steindl, Katharina; Institute of Medical Genetics, University of Zurich, 8952, Schlieren, Switzerland
Tedder, Matt ; Greenwood Genetic Center, Greenwood, IN, USA
Tessarech, Marine; Service de Génétique Médicale, CHU d'Angers, Angers, France ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France
Mau-Them, Frédéric Tran ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Trost, Detlef; Laboratoire Cerba, Saint-Ouen-l'Aumone, France
Van der Sluijs, Pleuntje J ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
Vincent, Marie ; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France ; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000, Nantes, France
Whalen, Sandra ; UF de Génétique Clinique et Centre de Référence Maladies Rares des Anomalies du Développement et Syndromes Malformatifs, ERN ITHACA, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France
Thauvin-Robinet, Christel ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Isidor, Bertrand; Nantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France ; Nantes Université, CHU de Nantes, Service de Génétique médicale, F-44000, Nantes, France
Sadikovic, Bekim ; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, Canada ; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada
Vitobello, Antonio ; Centre de Référence Anomalies Du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, 21000, Dijon, France ; Center of Genetics and Reference Centre for Intellectual Disabilities, Dijon Bourgogne University Hospital, Dijon, France
Colin, Estelle ; Service de Génétique Médicale, CHU d'Angers, Angers, France. escolin@chu-angers.fr ; Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France. escolin@chu-angers.fr
Funding for this study is provided in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). A.R. received funding by the University of Zurich clinical research priority program praeclare. Open access funding provided by Universit\u00E9 d\u2019Angers.
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