ARID2-related disorder: further delineation of the clinical phenotype of 27 novel individuals and description of an epigenetic signature

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.

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Publication Details

Journal
European Journal of Human Genetics
Published
2025-03-05
DOI
https://doi.org/10.1038/s41431-025-01798-w
Citations
4
Primary Topic
Chromatin Remodeling and Cancer
Type
article
Field-Weighted Citation Impact
3.22

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article

ARID2-related disorder: further delineation of the clinical phenotype of 27 novel individuals and description of an epigenetic signature

Valérie Cormier‐Daire, Gijs W.E. Santen, Boris Keren, Adeline Jacquinet et al.
4 citations
European Journal of Human Genetics
Chromatin Remodeling and Cancer
3.22
article

ARID2-related disorder: further delineation of the clinical phenotype of 27 novel individuals and description of an epigenetic signature

Valérie Cormier‐Daire, Gijs W.E. Santen, Boris Keren, Adeline Jacquinet, Christel Thauvin‐Robinet, Giulia Barcia, Frédéric Tran Mau‐Them, Tanguy Demaret, Alice Goldenberg, Beatrice Oneda, Sandra Whalen, Jennifer Schleit, Daniela Buhaş, Laurent Pasquier, Mélanie Fradin, Estelle Colin, Christophe Philippe, Sophie Rondeau, Katharina Steindl, Mathilde Nizon, Anita M. Rauch, Detlef Trost, Marie Bournez, Antoine Bonnevalle, Mariëlle Alders, Rebecca Procopio, Louis Legoff, Christèle Dubourg, Raissa Relator, Anaïs Begemann, Clément Prouteau, Antonio Vitobello, Ange‐Line Bruel, Pleuntje J. van der Sluijs, Karen W. Gripp, Liselot van der Laan, Himanshu Goel, Arthur Sorlin, Floriane Carallis, Marine Tessarech, Thomas Rambaud, Anne Guimier, Angela Bahr, Céline Bris, Marie Vincent, Bryce A. Mendelsohn, Dominique Bonneau, Bekim Sadiković, Cyril Mignot, Anne‐Sophie Denommé‐Pichon, Michael A. Levy, David Geneviève, Julie Désir, Aïcha Boughalem, Matthew L. Tedder, Kathleen Rooney, Clarisse Battault, Clara Houdayer, Haley McConkey, Vincent Procaccio, Vincent Milon, Bertrand Isidor, Benjamin Cogné, Julian Delanne, Agnès Guichet, Olivier Patat, Alice Bourges
article en
4 citations

Abstract

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.

European Journal of Human GeneticsVol. 33(11)
Western University (CA), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), DuPont (United States) (US), Inserm (FR), University of Liège (BE), Université de Bourgogne (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université de Montpellier (FR), University of Zurich (CH), Université Paris Cité (FR), Leiden University Medical Center (NL), London Health Sciences Centre (CA), Community Health Systems - Dupont Hospital (US), McGill University Health Centre (CA), Kaiser Permanente Oakland Medical Center (US), Centre Hospitalier Universitaire de Nantes (FR), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Assistance Publique – Hôpitaux de Paris (FR), Hunter Genetics (AU), Institute of Pathology and Genetics (BE), Centre Hospitalier Universitaire d'Angers (FR), CHU Dijon Bourgogne (FR), Centre d'Épidémiologie sur les Causes Médicales de Décès (FR), Institut du Thorax (FR), Greenwood Genetic Center (US), Amsterdam University Medical Centers (NL), Centre Hospitalier Universitaire de Rennes (FR), ERN ITHACA (FR), Université d'Angers (FR), McGill University (CA), Virbac (France) (FR), Université de Rouen Normandie (FR), Quest Diagnostics (United States) (US), University of Amsterdam (NL), Nantes Université (FR)
McGill University, Genome Canada, Ontario Genomics, McGill University Health Centre, Quest Diagnostics, Institut des maladies génétiques Imagine, Government of Canada, Ontario Genomics Institute, Institut National de la Santé et de la Recherche Médicale, Universiteit Leiden, Université de Bourgogne, Centre National de la Recherche Scientifique, Leids Universitair Medisch Centrum, Universität Zürich, Centre Hospitalier Universitaire de Nantes, Assistance publique-Hôpitaux de Paris, Normandie Université, Sorbonne Université
Quality Education
Openalex Percentile: Top 9%
Chromatin Remodeling and Cancer
3.22
DOIOpen Access PDFOpenAlex
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