Houdayer Clara, Rooney Kathleen, van der Laan Liselot, Bris Céline, Alders Mariëlle, Bahr Angela, Barcia Giulia, Battault Clarisse, Begemann Anais, Bonneau Dominique, Bonnevalle Antoine, Boughalem Aicha, Bourges Alice, Bournez Marie, Bruel Ange-Line, Buhas Daniela, Carallis Floriane, Cogné Benjamin, Cormier-Daire Valérie, Delanne Julian, Demaret Tanguy, Denommé-Pichon Anne-Sophie, Désir Julie, Dubourg Christèle, Fradin Mélanie, Geneviève David, Goel Himanshu, Goldenberg Alice, Gripp Karen W, Guichet Agnès, Guimier Anne, Jacquinet Adeline, Keren Boris, Legoff Louis, Levy Michael A, McConkey Haley, Mendelsohn Bryce A, Mignot Cyril, Milon Vincent, Nizon Mathilde, Oneda Beatrice, Pasquier Laurent, Patat Olivier, Philippe Christophe, Procaccio Vincent, Procopio Rebecca, Prouteau Clément, Rambaud Thomas, Rauch Anita, Relator Raissa, Rondeau Sophie, Santen Gijs W E, Schleit Jennifer, Sorlin Arthur, Steindl Katharina, Tedder Matt, Tessarech Marine, Mau-Them Frédéric Tran, Trost Detlef, Van der Sluijs Pleuntje J, Vincent Marie, Whalen Sandra, Thauvin-Robinet Christel, Isidor Bertrand, Sadikovic Bekim, Vitobello Antonio, Colin Estelle
Service de Génétique Médicale, CHU d'Angers, Angers, France.
Univ Angers, [CHU Angers], INSERM, CNRS, MITOVASC, SFR ICAT, F-49000, Angers, France.
Eur J Hum Genet. 2025 Mar 5. doi: 10.1038/s41431-025-01798-w.
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.
ARID2基因的罕见遗传变异导致了一种最近被描述的神经发育疾病，称为ARID2相关障碍（ARID2-RD）。ARID2属于PBAF，它是SWI/SNF复合体的一个亚单位，而SWI/SNF复合体是一种染色质重塑复合体。这项工作旨在进一步描绘ARID2-RD的表型谱，为临床医生提供更多数据，以便更好地护理并辅助未来对该疾病的诊断。我们获取了27例先前未报告的ARID2-RD患者的基因型和表型，并将该系列病例与文献中的研究结果进行比较。我们还评估了ARID2-RD患者外周血DNA甲基化谱，并与对照、未确诊病例及其他神经发育障碍的表观特征进行比较。ARID2-RD的主要临床特征包括发育迟缓、言语障碍、智力残疾、行为问题、身材矮小以及各种畸形和外胚层特征。全基因组差异甲基化分析显示，ARID2-RD存在整体高甲基化特征，这有助于对意义未明的变异进行重新分类。我们的研究使报告的携带ARID2致病变异的个体数量增加了一倍，达到53例。研究证实功能丧失是一种致病机制，且未发现明确的基因型-表型相关性。我们为ARID2-RD提供了独特的DNA甲基化表观特征的证据，并进一步描绘了ARID2相关的表型。
