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

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 KharbandaKatherine 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Purpose: 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 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 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 reanalysis, resulting in the reclassification of 2 ARID1A and 2 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.

Original language	English
Article number	101283
Journal	Genetics in Medicine
Volume	27
Issue number	1
Early online date	28 Sept 2024
DOIs	https://doi.org/10.1016/j.gim.2024.101283
Publication status	E-pub ahead of print - 28 Sept 2024

Keywords

ARID1A
ARID1B
BAF-complex
Intellectual Disability
duplication

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van der Sluijs, P. J., Moutton, S., Dingemans, A. J. M., Weis, D., Levy, M. A., Boycott, K. M., Arberas, C., Baldassarri, M., Beneteau, C., Brusco, A., Coutton, C., Dabir, T., Dentici, M. L., Devriendt, K., Faivre, L., van Haelst, M. M., Jizi, K., Kempers, M. J., Kerkhof, J., ... Santen, G. W. E. (2025). Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy. Genetics in Medicine, 27(1), Article 101283. Advance online publication. https://doi.org/10.1016/j.gim.2024.101283

@article{a9987f9631994dd59cdc9db776d81282,

title = "Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy",

abstract = "Purpose: 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 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 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 reanalysis, resulting in the reclassification of 2 ARID1A and 2 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",

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

year = "2024",

month = sep,

day = "28",

doi = "10.1016/j.gim.2024.101283",

language = "English",

volume = "27",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "1",

}

van der Sluijs, PJ, Moutton, S, Dingemans, AJM, Weis, D, Levy, MA, Boycott, KM, Arberas, C, Baldassarri, M, Beneteau, C, Brusco, A, Coutton, C, Dabir, T, Dentici, ML, Devriendt, K, Faivre, L, van Haelst, MM, Jizi, K, Kempers, MJ, Kerkhof, J, Kharbanda, M, Lachlan, K, Marle, N, McConkey, H, Mencarelli, MA, Mowat, D, Niceta, M, Nicolas, C, Novelli, A, Orlando, V, Pichon, O, Rankin, J, Relator, R, Ropers, FG, Rosenfeld, JA, Sachdev, R, Sandaradura, SA, Shukarova-Angelovska, E, Steenbeek, D, Tartaglia, M, Tedder, MA, Trajkova, S, Winer, N, Woods, J, de Vries, BBA, Sadikovic, B, Alders, M & Santen, GWE 2025, 'Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy', Genetics in Medicine, vol. 27, no. 1, 101283. https://doi.org/10.1016/j.gim.2024.101283

TY - JOUR

T1 - Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy

AU - van der Sluijs, Pleuntje J

AU - Moutton, Sébastien

AU - Dingemans, Alexander J M

AU - Weis, Denisa

AU - Levy, Michael A

AU - Boycott, Kym M

AU - Arberas, Claudia

AU - Baldassarri, Margherita

AU - Beneteau, Claire

AU - Brusco, Alfredo

AU - Coutton, Charles

AU - Dabir, Tabib

AU - Dentici, Maria L

AU - Devriendt, Koenraad

AU - Faivre, Laurence

AU - van Haelst, Mieke M

AU - Jizi, Khadije

AU - Kempers, Marlies J

AU - Kerkhof, Jennifer

AU - Kharbanda, Mira

AU - Lachlan, Katherine

AU - Marle, Nathalie

AU - McConkey, Haley

AU - Mencarelli, Maria A

AU - Mowat, David

AU - Niceta, Marcello

AU - Nicolas, Claire

AU - Novelli, Antonio

AU - Orlando, Valeria

AU - Pichon, Olivier

AU - Rankin, Julia

AU - Relator, Raissa

AU - Ropers, Fabienne G

AU - Rosenfeld, Jill A

AU - Sachdev, Rani

AU - Sandaradura, Sarah A

AU - Shukarova-Angelovska, Elena

AU - Steenbeek, Duco

AU - Tartaglia, Marco

AU - Tedder, Matthew A

AU - Trajkova, Slavica

AU - Winer, Norbert

AU - Woods, Jeremy

AU - de Vries, Bert B A

AU - Sadikovic, Bekim

AU - Alders, Marielle

AU - Santen, Gijs W E

PY - 2024/9/28

Y1 - 2024/9/28

N2 - Purpose: 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 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 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 reanalysis, resulting in the reclassification of 2 ARID1A and 2 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.

AB - Purpose: 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 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 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 reanalysis, resulting in the reclassification of 2 ARID1A and 2 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.

KW - ARID1A

KW - ARID1B

KW - BAF-complex

KW - Intellectual Disability

KW - duplication

U2 - 10.1016/j.gim.2024.101283

DO - 10.1016/j.gim.2024.101283

M3 - Article

SN - 1098-3600

VL - 27

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

M1 - 101283

ER -

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

Abstract

Keywords

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