Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SMARCA5 or SMARCA1 ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 have been previously implicated in NDDs. Here, we describe 35 individuals from 26 families with de novo or maternally inherited variants in the X-linked SMARCA1 gene. This SMARCA1-related NDD is associated with a spectrum of involvement, including mild to severe ID/DD, delayed or regressive speech development, ASD features, facial dysmorphisms, and other variable features. Individuals carrying SMARCA1 truncating variants exhibit a mildly unique genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptf single and double mouse knockouts reveals the importance of NURF composition and dosage for proper forebrain development. We propose that genetic alterations affecting different NURF components, including SMARCA1, result in a NDD with a broad clinical spectrum.

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Publication Details

Journal
Nature Communications
Published
2025-11-10
DOI
https://doi.org/10.1038/s41467-025-64838-5
Citations
4
Primary Topic
Chromatin Remodeling and Cancer
Type
article
Field-Weighted Citation Impact
3.22

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article

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

David J. Picketts, Sarah Weckhuysen, Juliette Piard, Stephan C. Collins et al.
4 citations
Nature Communications
Chromatin Remodeling and Cancer
3.22
article

Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

David J. Picketts, Sarah Weckhuysen, Juliette Piard, Stephan C. Collins, Sara Timpano, Nora Oyama, Kelly Bontempo, Zandrè Bruwer, Kyra E. Stuurman, Florence Démurger, Amy Goldstein, Noor Smal, Binnaz Yalcin, Peter Miny, Alberto Fernández‐Jaén, Kristen Park, Michael C. Kruer, Brad Angle, Solène Conrad, Raissa Relator, A. Micheil Innes, William B. Dobyns, Sirisak Chanprasert, Bertrand Isidor, Emily Pao, Lewis Pang, Mathieu Lévesque, Renske Oegema, Alfredo Brusco, Elisa Giorgio, Malin Kvarnung, Lori Carpenter, María Palomares‐Bralo, Pascal Joset, Dominique Bonneau, Bekim Sadiković, Sophie Nambot, María J. Guillen Sacoto, Daniel Martín Fernández‐Mayoralas, Vincenzo Antona, Emily O’Heir, Fernando Santos‐Simarro, Kirsten A. Donald, Wallid Deb, Elise Brischoux‐Boucher, Sarah A Paolucci, Rebecca C. Yeh, Antigone Papavasiliou, Katalin Štěrbová, Ghayda Mirzaa, Tjitske Kleefstra, Dong Li, Katherine Kim, Kristin G. Monaghan, Sébastien Moutton, Daniel C. Koboldt, Tawfeg Ben‐Omran, Alban Ziegler, Benjamin Cogné, Somayeh Bakhtiari, Barbara K. Burton, Emma Hobson, Parul Jayakar, K. Miller, Keqin Yan, P.S. Jayasinghe
article en
4 citations

Abstract

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SMARCA5 or SMARCA1 ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 have been previously implicated in NDDs. Here, we describe 35 individuals from 26 families with de novo or maternally inherited variants in the X-linked SMARCA1 gene. This SMARCA1-related NDD is associated with a spectrum of involvement, including mild to severe ID/DD, delayed or regressive speech development, ASD features, facial dysmorphisms, and other variable features. Individuals carrying SMARCA1 truncating variants exhibit a mildly unique genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptf single and double mouse knockouts reveals the importance of NURF composition and dosage for proper forebrain development. We propose that genetic alterations affecting different NURF components, including SMARCA1, result in a NDD with a broad clinical spectrum.

Nature CommunicationsVol. 16(1)
Broad Institute (US), Northwestern University (US), Western University (CA), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), University of Minnesota (US), Nationwide Children's Hospital (US), Barrow Neurological Institute (US), Karolinska University Hospital (SE), Children's Hospital of Philadelphia (US), University of Arizona (US), Radboud University Nijmegen (NL), University of Antwerp (BE), University of Ottawa (CA), Inserm (FR), University of Cape Town (ZA), University of Calgary (CA), Université de Bourgogne (FR), Utrecht University (NL), University of Washington (US), University of Pavia (IT), Chapel Allerton Hospital (GB), Leeds Teaching Hospitals NHS Trust (GB), Royal Devon & Exeter NHS Foundation Trust (GB), Ottawa Hospital (CA), London Health Sciences Centre (CA), Royal Devon and Exeter Hospital (GB), University of Washington Medical Center (US), Erasmus MC (NL), Alberta Children's Hospital (CA), University Hospital of Basel (CH), Radboud University Medical Center (NL), Karolinska Institutet (SE), University Medical Center Utrecht (NL), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire de Toulouse (FR), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Centre Hospitalier Universitaire de Besançon (FR), Norcliffe Foundation (US), Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT), University Hospital in Motol (CZ), Antwerp University Hospital (BE), Hospital La Paz Institute for Health Research (ES), Hospital Universitario Quirónsalud Madrid (ES), Department of Health (ES), Centre hospitalier Bretagne Atlantique (FR), Centre for Biomedical Network Research on Rare Diseases (ES), Centro de Investigación Biomédica en Red (ES), CHU Dijon Bourgogne (FR), Vincent Van Gogh Voor Geestelijke Gezondheidszorg (NL), Phoenix Children's Hospital (US), Lurie Children's Hospital (US), Health Research Institute of the Balearic Islands (ES), Sidra Medical and Research Center (QA), VIB-UAntwerp Center for Molecular Neurology (BE), Regenerative Medicine Institute (MX), Brotman Baty Institute (US), Saint Francis Health System (US), Institut du Thorax (FR), Miami Children's Hospital (US), Red Cross War Memorial Children's Hospital (ZA), Génétique Médicale & Génomique Fonctionelle (FR), Iaso Children’s Hospital (GR), Advocate Children's Hospital (US), Ottawa Hospital Research Institute (CA), Université d'Angers (FR), Hamad Medical Corporation (QA), University of Turin (IT), University of Pennsylvania (US), University of Palermo (IT), Universidad Europea de Madrid (ES), University of Colorado Denver (US), Ottawa University (US), Nantes Université (FR)
University of Ottawa, Genome Canada, Seattle Children's Research Institute, Children’s Hospital of Wisconsin Research Institute, Children's Hospital Foundation, Ontario Genomics, Broad Institute, Simons Foundation Autism Research Initiative, Ontario Genomics Institute, Genome British Columbia, Fonds National de la Recherche Luxembourg, Alberta Children's Hospital Foundation, Ministero dell’Istruzione, dell’Università e della Ricerca, Genome Alberta, Vlaamse regering, National Institutes of Health, Qatar National Research Fund, Stanley Center for Psychiatric Research, Broad Institute, Canadian Institutes of Health Research, National Institute of Mental Health
Openalex Percentile: Top 7%
Chromatin Remodeling and Cancer
3.22
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