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

David Picketts; Ghayda Mirzaa; Keqin Yan; Raissa Relator; Sara Timpano; Binnaz Yalcin; Stephan Collins; Alban Ziegler; Emily Pao; Nora Oyama; Elise Brischoux-Boucher; Juliette Piard; Kristin Monaghan; Maria Guillen Sacoto; William Dobyns; Kristen Park; Daniel Fernández-Mayoralas; Alberto Fernández-Jaén; Parul Jayakar; Alfredo Brusco; Vincenzo Antona; Elisa Giorgio; Malin Kvarnung; Bertrand Isidor; Solène Conrad; Benjamin Cogné; Wallid Deb; K E Stuurman; Katalin Sterbova; Noor Smal; Sarah Weckhuysen; Renske Oegema; Micheil Innes; Maeson Latsko; Tawfeg Ben-Omran; Rebecca Yeh; Michael Kruer; Somayeh Bakhtiari; Antigone Papavasiliou; Sébastien Moutton; Sophie Nambot; Sirisak Chanprasert; Sarah Paolucci; Kait Miller; Barbara Burton; Katherine Kim; Emily O'Heir; Zandre Bruwer; Kirsten 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

doi:10.21203/rs.3.rs-3317938/v1

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

David Picketts, Ghayda Mirzaa, Keqin Yan, Raissa Relator, Sara Timpano, Binnaz Yalcin, Stephan Collins, Alban Ziegler, Emily Pao, Nora Oyama, Elise Brischoux-Boucher, Juliette Piard, Kristin Monaghan, Maria Guillen Sacoto, William Dobyns, Kristen Park, Daniel Fernández-Mayoralas, Alberto Fernández-Jaén, Parul Jayakar, Alfredo BruscoVincenzo Antona, Elisa Giorgio, Malin Kvarnung, Bertrand Isidor, Solène Conrad, Benjamin Cogné, Wallid Deb, K E Stuurman, Katalin Sterbova, Noor Smal, Sarah Weckhuysen, Renske Oegema, Micheil Innes, Maeson Latsko, Tawfeg Ben-Omran, Rebecca Yeh, Michael Kruer, Somayeh Bakhtiari, Antigone Papavasiliou, Sébastien Moutton, Sophie Nambot, Sirisak Chanprasert, Sarah Paolucci, Kait Miller, Barbara Burton, Katherine Kim, Emily O'Heir, Zandre Bruwer, Kirsten 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

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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 SNF2H ( SMARCA5) or SNF2L ( SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

Original language	English
Publisher	Research Square
Number of pages	32
DOIs	https://doi.org/10.21203/rs.3.rs-3317938/v1
Publication status	Published - 29 Sept 2023

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Picketts, D., Mirzaa, G., Yan, K., Relator, R., Timpano, S., Yalcin, B., Collins, S., Ziegler, A., Pao, E., Oyama, N., Brischoux-Boucher, E., Piard, J., Monaghan, K., Sacoto, M. G., Dobyns, W., Park, K., Fernández-Mayoralas, D., Fernández-Jaén, A., Jayakar, P., ... Sadikovic, B. (2023). Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition. (Research square). Research Square. https://doi.org/10.21203/rs.3.rs-3317938/v1

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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 SNF2H ( SMARCA5) or SNF2L ( SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum. ",

author = "David Picketts and Ghayda Mirzaa and Keqin Yan and Raissa Relator 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 Kristin Monaghan and Sacoto, {Maria Guillen} and William Dobyns and Kristen Park and Daniel Fern{\'a}ndez-Mayoralas and Alberto Fern{\'a}ndez-Ja{\'e}n and Parul Jayakar 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, {K E} and Katalin Sterbova and Noor Smal and Sarah Weckhuysen and Renske Oegema and Micheil Innes and Maeson Latsko and Tawfeg Ben-Omran and Rebecca Yeh and Michael Kruer and Somayeh Bakhtiari and Antigone Papavasiliou and S{\'e}bastien Moutton and Sophie Nambot and Sirisak Chanprasert and Sarah Paolucci and Kait Miller and Barbara Burton and Katherine Kim and Emily O'Heir and Zandre Bruwer and Kirsten Donald 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",

year = "2023",

month = sep,

day = "29",

doi = "10.21203/rs.3.rs-3317938/v1",

language = "English",

series = "Research square",

publisher = "Research Square",

type = "WorkingPaper",

institution = "Research Square",

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Picketts, D, Mirzaa, G, Yan, K, Relator, R, Timpano, S, Yalcin, B, Collins, S, Ziegler, A, Pao, E, Oyama, N, Brischoux-Boucher, E, Piard, J, Monaghan, K, Sacoto, MG, Dobyns, W, Park, K, Fernández-Mayoralas, D, Fernández-Jaén, A, Jayakar, P, Brusco, A, Antona, V, Giorgio, E, Kvarnung, M, Isidor, B, Conrad, S, Cogné, B, Deb, W, Stuurman, KE, Sterbova, K, Smal, N, Weckhuysen, S, Oegema, R, Innes, M, Latsko, M, Ben-Omran, T, Yeh, R, Kruer, M, Bakhtiari, S, Papavasiliou, A, Moutton, S, Nambot, S, Chanprasert, S, Paolucci, S, Miller, K, Burton, B, Kim, K, O'Heir, E, Bruwer, Z, Donald, K, 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 2023 'Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition' Research square, Research Square. https://doi.org/10.21203/rs.3.rs-3317938/v1

TY - UNPB

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

AU - Picketts, David

AU - Mirzaa, Ghayda

AU - Yan, Keqin

AU - Relator, Raissa

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

AU - Sacoto, Maria Guillen

AU - Dobyns, William

AU - Park, Kristen

AU - Fernández-Mayoralas, Daniel

AU - Fernández-Jaén, Alberto

AU - Jayakar, Parul

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, K E

AU - Sterbova, Katalin

AU - Smal, Noor

AU - Weckhuysen, Sarah

AU - Oegema, Renske

AU - Innes, Micheil

AU - Latsko, Maeson

AU - Ben-Omran, Tawfeg

AU - Yeh, Rebecca

AU - Kruer, Michael

AU - Bakhtiari, Somayeh

AU - Papavasiliou, Antigone

AU - Moutton, Sébastien

AU - Nambot, Sophie

AU - Chanprasert, Sirisak

AU - Paolucci, Sarah

AU - Miller, Kait

AU - Burton, Barbara

AU - Kim, Katherine

AU - O'Heir, Emily

AU - Bruwer, Zandre

AU - Donald, Kirsten

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

PY - 2023/9/29

Y1 - 2023/9/29

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 SNF2H ( SMARCA5) or SNF2L ( SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components 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 SNF2H ( SMARCA5) or SNF2L ( SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

U2 - 10.21203/rs.3.rs-3317938/v1

DO - 10.21203/rs.3.rs-3317938/v1

M3 - Preprint

C2 - 37841849

T3 - Research square

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

PB - Research Square

ER -

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

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