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

ARID1A ARID1B BAF-complex Intellectual Disability duplication

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
28 Sep 2024
Historique:
received: 20 03 2024
revised: 23 09 2024
accepted: 23 09 2024
medline: 2 10 2024
pubmed: 2 10 2024
entrez: 2 10 2024
Statut: aheadofprint

Résumé

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

Sections du résumé

BACKGROUND 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 METHODS
We collected patients with duplications encompassing ARID1A and ARID1B duplications.
RESULTS 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 CONCLUSIONS
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.

Identifiants

DOI: 10.1016/j.gim.2024.101283 PMID: 39355979
pubmed: 39355979
pii: S1098-3600(24)00217-X
doi: 10.1016/j.gim.2024.101283
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101283

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Pleuntje J van der Sluijs (PJ)

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Sébastien Moutton (S)

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.

Alexander J M Dingemans (AJM)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Denisa Weis (D)

Institute of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University Linz, Linz, Austria.

Michael A Levy (MA)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.

Kym M Boycott (KM)

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.

Claudia Arberas (C)

Sección Genética Médica, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina.

Margherita Baldassarri (M)

Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy.

Claire Beneteau (C)

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.

Alfredo Brusco (A)

Department of Medical Sciences, University of Torino, Torino, Italy.

Charles Coutton (C)

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.

Tabib Dabir (T)

Department of Genetic Medicine, Belfast City Hospital, Belfast, Northern Ireland, UK.

Maria L Dentici (ML)

Medical Genetics, IRCCS Bambino Gesù Children Hospital, Rome, Italy.

Koenraad Devriendt (K)

Center for Human Genetics, University Hospitals Leuven, Leuven.

Laurence Faivre (L)

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.

Mieke M van Haelst (MM)

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.

Khadije Jizi (K)

Department of Pediatrics, Université de Montréal, Montreal, QC, Canada; Centre de recherche et Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.

Marlies J Kempers (MJ)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Jennifer Kerkhof (J)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.

Mira Kharbanda (M)

Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.

Katherine Lachlan (K)

Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.

Nathalie Marle (N)

Laboratoire de Génétique Chromosomique et Moléculaire, Pôle de Biologie, CHU de Dijon, Dijon, France.

Haley McConkey (H)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Maria A Mencarelli (MA)

Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

David Mowat (D)

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.

Marcello Niceta (M)

Molecular Genetics and Functional Genomics, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Claire Nicolas (C)

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.

Antonio Novelli (A)

Translational Cytogenomics, IRCCS Bambino Gesù Children Hospital, Rome, Italy.

Valeria Orlando (V)

Translational Cytogenomics, IRCCS Bambino Gesù Children Hospital, Rome, Italy.

Olivier Pichon (O)

Service de Génétique médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.

Julia Rankin (J)

Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

Raissa Relator (R)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.

Fabienne G Ropers (FG)

Willem-Alexander Children's Hospital, department of Pediatrics, Leiden University Medical Center, the Netherlands.

Jill A Rosenfeld (JA)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Baylor Genetics Laboratories, Houston, TX, USA.

Rani Sachdev (R)

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.

Sarah A Sandaradura (SA)

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.

Elena Shukarova-Angelovska (E)

Department of Endocrinology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of North Macedonia.

Duco Steenbeek (D)

Department of Rehabilitation Medicine, Maastricht University Medical Center / Adelante Rehabilitation, Maastricht, The Netherlands.

Marco Tartaglia (M)

Center for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.

Matthew A Tedder (MA)

Greenwood Genetic Center, Greenwood, SC, USA.

Slavica Trajkova (S)

Department of Medical Sciences, University of Torino, Torino, Italy; Molecular Biotechnology Center "Guido Tarone University of Turin, Turin, Italy.

Norbert Winer (N)

Service de Gynécologie-Obstétrique, Centre Hospitalier Universitaire de Nantes, Nantes, France; NUN, INRAE, UMR 1280, PhAN, Université de Nantes, F-44000 Nantes, France.

Jeremy Woods (J)

Department of Genetics, Valley Childrens Hospital, Madera, CA, USA; Stanford University, Palo Alto, CA, USA.

Bert B A de Vries (BBA)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Bekim Sadikovic (B)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Marielle Alders (M)

Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Gijs W E Santen (GWE)

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: santen@lumc.nl.

Classifications MeSH