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; David J. Picketts

doi:10.1038/s41467-025-64838-5

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 JayakarMaría 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, David J. Picketts^*

^*Corresponding author for this work

Clinical Genetics

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

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.

Original language	English
Article number	9875
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-64838-5
Publication status	Published - 10 Nov 2025

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Publisher Copyright: © The Author(s) 2025.

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Mirzaa, G. M., Yan, K., Relator, R., Levesque, M., Jayasinghe, P., Timpano, S., Yalcin, B., Collins, S., Ziegler, A., Pao, E., Oyama, N., Brischoux-Boucher, E., Piard, J., Monaghan, K. G., Guillen Sacoto, M. J., Dobyns, W. B., Park, K. L., Fernández-Mayoralas, D. M., Fernández-Jaén, A., ... Picketts, D. J. (2025). Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition. Nature Communications, 16(1), Article 9875. https://doi.org/10.1038/s41467-025-64838-5

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

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.",

author = "Mirzaa, \{Ghayda M.\} and Keqin Yan and Raissa Relator and Mathieu Levesque and Pranisha Jayasinghe and Sara Timpano and Binnaz Yalcin and Stephan Collins and Alban Ziegler and Emily Pao and Nora Oyama and Elise Brischoux-Boucher and Juliette Piard and Monaghan, \{Kristin G.\} and \{Guillen Sacoto\}, \{Maria J.\} and Dobyns, \{William B.\} and Park, \{Kristen L.\} and Fern{\'a}ndez-Mayoralas, \{Daniel Martin\} and Alberto Fern{\'a}ndez-Ja{\'e}n and Parul Jayakar and Mar{\'i}a Palomares-Bralo and Fernando Santos-Simarro and Alfredo Brusco and Vincenzo Antona and Elisa Giorgio and Malin Kvarnung and Bertrand Isidor and Sol{\`e}ne Conrad and Benjamin Cogn{\'e} and Wallid Deb and Stuurman, \{Kyra E.\} and Katalin {\v S}t{\v e}rbov{\'a} and Noor Smal and Sarah Weckhuysen and Renske Oegema and Innes, \{A. Micheil\} and Koboldt, \{Daniel C.\} and Tawfeg Ben-Omran and Yeh, \{Rebecca C.\} and Kruer, \{Michael C.\} and Somayeh Bakhtiari and Antigone Papavasiliou and S{\'e}bastien Moutton and Sophie Nambot and Sirisak Chanprasert and Paolucci, \{Sarah A.\} and Kait Miller and Barbara Burton and Katherine Kim and Emily O{\textquoteright}Heir and Zandre Bruwer and Donald, \{Kirsten A.\} and Tjitske Kleefstra and Amy Goldstein and Brad Angle and Kelly Bontempo and Peter Miny and Pascal Joset and Florence Demurger and Emma Hobson and Lewis Pang and Lori Carpenter and Dong Li and Dominique Bonneau and Bekim Sadikovic and Picketts, \{David J.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = nov,

day = "10",

doi = "10.1038/s41467-025-64838-5",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

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Mirzaa, GM, Yan, K, Relator, R, Levesque, M, Jayasinghe, P, Timpano, S, Yalcin, B, Collins, S, Ziegler, A, Pao, E, Oyama, N, Brischoux-Boucher, E, Piard, J, Monaghan, KG, Guillen Sacoto, MJ, Dobyns, WB, Park, KL, Fernández-Mayoralas, DM, Fernández-Jaén, A, Jayakar, P, Palomares-Bralo, M, Santos-Simarro, F, Brusco, A, Antona, V, Giorgio, E, Kvarnung, M, Isidor, B, Conrad, S, Cogné, B, Deb, W, Stuurman, KE, Štěrbová, K, Smal, N, Weckhuysen, S, Oegema, R, Innes, AM, Koboldt, DC, Ben-Omran, T, Yeh, RC, Kruer, MC, Bakhtiari, S, Papavasiliou, A, Moutton, S, Nambot, S, Chanprasert, S, Paolucci, SA, Miller, K, Burton, B, Kim, K, O’Heir, E, Bruwer, Z, Donald, KA, Kleefstra, T, Goldstein, A, Angle, B, Bontempo, K, Miny, P, Joset, P, Demurger, F, Hobson, E, Pang, L, Carpenter, L, Li, D, Bonneau, D, Sadikovic, B & Picketts, DJ 2025, 'Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition', Nature Communications, vol. 16, no. 1, 9875. https://doi.org/10.1038/s41467-025-64838-5

TY - JOUR

T1 - Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

AU - Mirzaa, Ghayda M.

AU - Yan, Keqin

AU - Relator, Raissa

AU - Levesque, Mathieu

AU - Jayasinghe, Pranisha

AU - Timpano, Sara

AU - Yalcin, Binnaz

AU - Collins, Stephan

AU - Ziegler, Alban

AU - Pao, Emily

AU - Oyama, Nora

AU - Brischoux-Boucher, Elise

AU - Piard, Juliette

AU - Monaghan, Kristin G.

AU - Guillen Sacoto, Maria J.

AU - Dobyns, William B.

AU - Park, Kristen L.

AU - Fernández-Mayoralas, Daniel Martin

AU - Fernández-Jaén, Alberto

AU - Jayakar, Parul

AU - Palomares-Bralo, María

AU - Santos-Simarro, Fernando

AU - Brusco, Alfredo

AU - Antona, Vincenzo

AU - Giorgio, Elisa

AU - Kvarnung, Malin

AU - Isidor, Bertrand

AU - Conrad, Solène

AU - Cogné, Benjamin

AU - Deb, Wallid

AU - Stuurman, Kyra E.

AU - Štěrbová, Katalin

AU - Smal, Noor

AU - Weckhuysen, Sarah

AU - Oegema, Renske

AU - Innes, A. Micheil

AU - Koboldt, Daniel C.

AU - Ben-Omran, Tawfeg

AU - Yeh, Rebecca C.

AU - Kruer, Michael C.

AU - Bakhtiari, Somayeh

AU - Papavasiliou, Antigone

AU - Moutton, Sébastien

AU - Nambot, Sophie

AU - Chanprasert, Sirisak

AU - Paolucci, Sarah A.

AU - Miller, Kait

AU - Burton, Barbara

AU - Kim, Katherine

AU - O’Heir, Emily

AU - Bruwer, Zandre

AU - Donald, Kirsten A.

AU - Kleefstra, Tjitske

AU - Goldstein, Amy

AU - Angle, Brad

AU - Bontempo, Kelly

AU - Miny, Peter

AU - Joset, Pascal

AU - Demurger, Florence

AU - Hobson, Emma

AU - Pang, Lewis

AU - Carpenter, Lori

AU - Li, Dong

AU - Bonneau, Dominique

AU - Sadikovic, Bekim

AU - Picketts, David J.

PY - 2025/11/10

Y1 - 2025/11/10

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105021290067

U2 - 10.1038/s41467-025-64838-5

DO - 10.1038/s41467-025-64838-5

M3 - Article

C2 - 41213919

AN - SCOPUS:105021290067

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 9875

ER -

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

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