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

Ghayda M. Mirzaa (), Keqin Yan, Raissa Relator, Mathieu Levesque, Pranisha Jayasinghe, Sara Timpano, Binnaz Yalcin, Stephan Collins, Alban Ziegler, Emily Pao, Nora Oyama, Elise Brischoux-Boucher, Juliette Piard, Kristin G. Monaghan, Maria. J. Guillen Sacoto, William B. Dobyns, Kristen L. Park, Daniel Martin Fernández-Mayoralas, Alberto Fernández-Jaén, Parul Jayakar, María Palomares-Bralo, Fernando Santos-Simarro, Alfredo Brusco, Vincenzo Antona, Elisa Giorgio, Malin Kvarnung, Bertrand Isidor, Solène Conrad, Benjamin Cogné, Wallid Deb, Kyra E. Stuurman, Katalin Štěrbová, Noor Smal, Sarah Weckhuysen, Renske Oegema, A. Micheil Innes, Daniel. C. Koboldt, Tawfeg Ben-Omran, Rebecca C. Yeh, Michael C. Kruer, Somayeh Bakhtiari, Antigone Papavasiliou, Sébastien Moutton, Sophie Nambot, Sirisak Chanprasert, Sarah A. Paolucci, Kait Miller, Barbara Burton, Katherine Kim, Emily O’Heir, Zandre Bruwer, Kirsten. A. Donald, Tjitske Kleefstra, Amy Goldstein, Brad Angle, Kelly Bontempo, Peter Miny, Pascal Joset, Florence Demurger, Emma Hobson, Lewis Pang, Lori Carpenter, Dong Li, Dominique Bonneau, Bekim Sadikovic and David J. Picketts ()
Additional contact information
Ghayda M. Mirzaa: Seattle Children’s Research Institute
Keqin Yan: Ottawa Hospital Research Institute
Raissa Relator: London Health Sciences Centre
Mathieu Levesque: Ottawa Hospital Research Institute
Pranisha Jayasinghe: Ottawa Hospital Research Institute
Sara Timpano: Ottawa Hospital Research Institute
Binnaz Yalcin: University of Bourgogne
Stephan Collins: University of Bourgogne
Alban Ziegler: CHU de Toulouse
Emily Pao: Seattle Children’s Research Institute
Nora Oyama: Seattle Children’s Research Institute
Elise Brischoux-Boucher: Centre Hospitalier Universitaire de Besançon
Juliette Piard: Centre Hospitalier Universitaire de Besançon
Kristin G. Monaghan: GeneDx
Maria. J. Guillen Sacoto: GeneDx
William B. Dobyns: University of Minnesota
Kristen L. Park: University of Colorado School of Medicine
Daniel Martin Fernández-Mayoralas: Hospital Universitario Quirónsalud
Alberto Fernández-Jaén: Hospital Universitario Quirónsalud
Parul Jayakar: Nicklaus Children’s Hospital
María Palomares-Bralo: Institute of Medical and Molecular Genetics
Fernando Santos-Simarro: Health Research Institute of the Balearic Islands (IdISBa)
Alfredo Brusco: University of Turin
Vincenzo Antona: ” University of Palermo
Elisa Giorgio: University of Pavia
Malin Kvarnung: Karolinska Institutet
Bertrand Isidor: Nantes Université, CHU de Nantes, CNRS, INSERM, L’institut du thorax
Solène Conrad: Nantes Université, CHU de Nantes, CNRS, INSERM, L’institut du thorax
Benjamin Cogné: Nantes Université, CHU de Nantes, CNRS, INSERM, L’institut du thorax
Wallid Deb: Nantes Université, CHU de Nantes, CNRS, INSERM, L’institut du thorax
Kyra E. Stuurman: Erasmus MC University Medical Center
Katalin Štěrbová: University Hospital Motol
Noor Smal: VIB
Sarah Weckhuysen: VIB
Renske Oegema: Utrecht University
A. Micheil Innes: University of Calgary
Daniel. C. Koboldt: Nationwide Children’s Hospital
Tawfeg Ben-Omran: Hamad Medical Corporation
Rebecca C. Yeh: Boston Children’s Hospital
Michael C. Kruer: Phoenix Children’s Hospital
Somayeh Bakhtiari: Phoenix Children’s Hospital
Antigone Papavasiliou: IASO Children’s Hospital
Sébastien Moutton: CHU François Mitterrand
Sophie Nambot: CHU François Mitterrand
Sirisak Chanprasert: University of Washington
Sarah A. Paolucci: University of Washington
Kait Miller: University of Washington School of Medicine
Barbara Burton: Northwestern University Feinberg School of Medicine
Katherine Kim: Northwestern University Feinberg School of Medicine
Emily O’Heir: Broad Institute of MIT
Zandre Bruwer: University of Cape Town
Kirsten. A. Donald: University of Cape Town
Tjitske Kleefstra: Radboud University Medical Center
Amy Goldstein: Children’s Hospital of Philadelphia
Brad Angle: Advocate Children’s Hospital
Kelly Bontempo: Advocate Children’s Hospital
Peter Miny: University Hospital Basel
Pascal Joset: University Hospital Basel
Florence Demurger: CHBA
Emma Hobson: Leeds Teaching Hospitals NHS Trust
Lewis Pang: Royal Devon and Exeter
Lori Carpenter: Inc
Dong Li: University of Pennsylvania
Dominique Bonneau: CHU de Toulouse
Bekim Sadikovic: London Health Sciences Centre
David J. Picketts: Ottawa Hospital Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64838-5

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