Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy

Pleuntje J van der Sluijs; Sébastien Moutton; Alexander J M Dingemans; Denisa Weis; Michael A Levy; Kym M Boycott; Claudia Arberas; Margherita Baldassarri; Claire Beneteau; Alfredo Brusco; Charles Coutton; Tabib Dabir; Maria L Dentici; Koenraad Devriendt; Laurence Faivre; Mieke M van Haelst; Khadije Jizi; Marlies J Kempers; Jennifer Kerkhof; Mira Kharbanda; Katherine Lachlan; Nathalie Marle; Haley McConkey; Maria A Mencarelli; David Mowat; Marcello Niceta; Claire Nicolas; Antonio Novelli; Valeria Orlando; Olivier Pichon; Julia Rankin; Raissa Relator; Fabienne G Ropers; Jill A Rosenfeld; Rani Sachdev; Sarah A Sandaradura; Elena Shukarova-Angelovska; Duco Steenbeek; Marco Tartaglia; Matthew A Tedder; Slavica Trajkova; Norbert Winer; Jeremy Woods; Bert B A de Vries; Bekim Sadikovic; Marielle Alders; Gijs W E Santen

doi:10.1016/j.gim.2024.101283

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy

Genet Med. 2024 Sep 28:101283. doi: 10.1016/j.gim.2024.101283. Online ahead of print.

Authors

Pleuntje J van der Sluijs¹, Sébastien Moutton², Alexander J M Dingemans³, Denisa Weis⁴, Michael A Levy⁵, Kym M Boycott⁶, Claudia Arberas⁷, Margherita Baldassarri⁸, Claire Beneteau⁹, Alfredo Brusco¹⁰, Charles Coutton¹¹, Tabib Dabir¹², Maria L Dentici¹³, Koenraad Devriendt¹⁴, Laurence Faivre¹⁵, Mieke M van Haelst¹⁶, Khadije Jizi¹⁷, Marlies J Kempers³, Jennifer Kerkhof⁵, Mira Kharbanda¹⁸, Katherine Lachlan¹⁹, Nathalie Marle²⁰, Haley McConkey²¹, Maria A Mencarelli²², David Mowat²³, Marcello Niceta²⁴, Claire Nicolas¹⁵, Antonio Novelli²⁵, Valeria Orlando²⁵, Olivier Pichon²⁶, Julia Rankin²⁷, Raissa Relator⁵, Fabienne G Ropers²⁸, Jill A Rosenfeld²⁹, Rani Sachdev³⁰, Sarah A Sandaradura³¹, Elena Shukarova-Angelovska³², Duco Steenbeek³³, Marco Tartaglia³⁴, Matthew A Tedder³⁵, Slavica Trajkova³⁶, Norbert Winer³⁷, Jeremy Woods³⁸, Bert B A de Vries³, Bekim Sadikovic²¹, Marielle Alders³⁹, Gijs W E Santen⁴⁰

Affiliations

¹ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
² CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France.
³ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ Institute of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University Linz, Linz, Austria.
⁵ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
⁶ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
⁷ Sección Genética Médica, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina.
⁸ Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy.
⁹ Service de Génétique médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France; Centre Hospitalier Universitaire de Nantes, UF de Foetopathologie et Génétique, Nantes, France; Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
¹⁰ Department of Medical Sciences, University of Torino, Torino, Italy.
¹¹ Service de Génétique, Génomique, et Procréation, Centre Hospitalier Universitaire Grenoble Alpes, La Tronche, France; INSERM 1209, CNRS UMR 5309, Institut pour l'Avancée des Biosciences (IAB), Université Grenoble Alpes, Grenoble, France.
¹² Department of Genetic Medicine, Belfast City Hospital, Belfast, Northern Ireland, UK.
¹³ Medical Genetics, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
¹⁴ Center for Human Genetics, University Hospitals Leuven, Leuven.
¹⁵ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France; Genetics of Developmental Disorders, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Dijon, France.
¹⁶ Section Clinical Genetics, Department of Human Genetics, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Amsterdam Reproduction and Development, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
¹⁷ Department of Pediatrics, Université de Montréal, Montreal, QC, Canada; Centre de recherche et Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
¹⁸ Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.
¹⁹ Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
²⁰ Laboratoire de Génétique Chromosomique et Moléculaire, Pôle de Biologie, CHU de Dijon, Dijon, France.
²¹ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
²² Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
²³ Center for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia; University of New South Wales, School of Women's and Children's Health, Faculty of Medicine and Health, Kensington, New South Wales, Australia.
²⁴ Molecular Genetics and Functional Genomics, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
²⁵ Translational Cytogenomics, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
²⁶ Service de Génétique médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
²⁷ Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
²⁸ Willem-Alexander Children's Hospital, department of Pediatrics, Leiden University Medical Center, the Netherlands.
²⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA.
³⁰ University of New South Wales, School of Women's and Children's Health, Faculty of Medicine and Health, Kensington, New South Wales, Australia; School of Women's and Children's Health, UNSW Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
³¹ Sydney Children's Hospitals Network - Westmead, Sydney, New South Wales, Australia; Children's Hospital Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia.
³² Department of Endocrinology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of North Macedonia.
³³ Department of Rehabilitation Medicine, Maastricht University Medical Center / Adelante Rehabilitation, Maastricht, The Netherlands.
³⁴ Center for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.
³⁵ Greenwood Genetic Center, Greenwood, SC, USA.
³⁶ Department of Medical Sciences, University of Torino, Torino, Italy; Molecular Biotechnology Center "Guido Tarone University of Turin, Turin, Italy.
³⁷ Service de Gynécologie-Obstétrique, Centre Hospitalier Universitaire de Nantes, Nantes, France; NUN, INRAE, UMR 1280, PhAN, Université de Nantes, F-44000 Nantes, France.
³⁸ Department of Genetics, Valley Childrens Hospital, Madera, CA, USA; Stanford University, Palo Alto, CA, USA.
³⁹ Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
⁴⁰ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: [email protected].

PMID: 39355979
DOI: 10.1016/j.gim.2024.101283

Abstract

Background: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype.

Methods: We collected patients with duplications encompassing ARID1A and ARID1B duplications.

Results: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic.

Conclusion: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency.

Keywords: ARID1A; ARID1B; BAF-complex; Intellectual Disability; duplication.