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<p>Rare genetic variants in <i>ARID2</i> 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 <i>ARID2</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月5日

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

摘要

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.