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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.

SUBMITTER: Picketts D 

PROVIDER: S-EPMC10571636 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Picketts David D   Mirzaa Ghayda G   Yan Keqin K   Relator Raissa R   Timpano Sara S   Yalcin Binnaz B   Collins Stephan S   Ziegler Alban A   Pao Emily E   Oyama Nora N   Brischoux-Boucher Elise E   Piard Juliette J   Monaghan Kristin K   Sacoto Maria Guillen MG   Dobyns William W   Park Kristen K   Fernández-Mayoralas Daniel D   Fernández-Jaén Alberto A   Jayakar Parul P   Brusco Alfredo A   Antona Vincenzo V   Giorgio Elisa E   Kvarnung Malin M   Isidor Bertrand B   Conrad Solène S   Cogné Benjamin B   Deb Wallid W   Stuurman K E KE   Sterbova Katalin K   Smal Noor N   Weckhuysen Sarah S   Oegema Renske R   Innes Micheil M   Latsko Maeson M   Ben-Omran Tawfeg T   Yeh Rebecca R   Kruer Michael M   Bakhtiari Somayeh S   Papavasiliou Antigone A   Moutton Sébastien S   Nambot Sophie S   Chanprasert Sirisak S   Paolucci Sarah S   Miller Kait K   Burton Barbara B   Kim Katherine K   O'Heir Emily E   Bruwer Zandre Z   Donald Kirsten K   Kleefstra Tjitske T   Goldstein Amy A   Angle Brad B   Bontempo Kelly K   Miny Peter P   Joset Pascal P   Demurger Florence F   Hobson Emma E   Pang Lewis L   Carpenter Lori L   Li Dong D   Bonneau Dominique D   Sadikovic Bekim B  

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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 (<i>SMARCA5</i>) or SNF2L (<i>SMARCA1</i>) ISWI-chromatin remodeling enzyme. Pathogenic variants in <i>BPTF</i> and <i>SMARCA5</i> were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with <i>de novo</i> or maternally inherited pathogenic variants in <i>SMARCA1</i>. This novel NDD w  ...[more]

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