Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Machol, Keren; Rousseau, Justine; Ehresmann, Sophie; Garcia, Thomas; Nguyen, Thi Tuyet Mai; Fiala, Elise; Willing, Marcia; Pfundt, Rolph; Kleefstra, Tjitske; Cho, Megan T.; McLaughlin, Heather; Piera, Monica Rosello; Orellana, Carmen; Martı́nez, Francisco; Caro-Llopis, Alfonso; Monfort, Sandra; Roscioli, Tony; Nixon, Cheng Yee; Buckley, Michael F.; Turner, Anne; Jones, Wendy D.; Hasselt, Peter M. van; Hofstede, Floris C.; Gassen, Koen van; Brooks, Alice S.; Slegtenhorst, Marjon A. van; Lachlan, Katherine; Sebastian, Jessica; Madan‐Khetarpal, Suneeta; Desai, Sonal; Naidu, Sakkubai; Thévenon, Julien; Faivre, Laurence; Maurel, Alice; Petrovski, Steve; Krantz, Ian D.; Tarpinian, Jennifer; Campeau, Philippe M.; Adams, David R.; Alejandro, Mercedes E.; Allard, Patrick; Azamian, Mahshid S.; Bacino, Carlos A.; Balasubramanyam, Ashok; Barseghyan, Hayk; Batzli, Gabriel F.; Beggs, Alan H.; Behnam, Babak; Bican, Anna; Bick, David; Birch, Camille L.; Bonner, Devon; Boone, Braden; Bostwick, Bret L.; Briere, Lauren C.; Brown, Donna M.; Brush, Matthew; Burke, Elizabeth; Burrage, Lindsay C.; Chen, Shan; Clark, Gary D.; Coakley, Terra R.; Cogan, Joy D.; Cooper, Cynthia; Cope, Heidi; Craigen, William J.; D’Souza, Precilla; Davids, Mariska; Dayal, Jyoti G.; Dell’Angelica, Esteban C.; Dhar, Shweta U.; Dillon, Ani; Dipple, Katrina M.; Donnell‐Fink, Laurel A.; Dorrani, Naghmeh; Dorset, Daniel C.; Douine, Emilie D.; Draper, David D.; Eckstein, David J.; Emrick, Lisa; Eng, Christine M.; Eskin, Ascia; Esteves, Cecilia; Estwick, Tyra; Ferreira, Carlos R.; Fogel, Brent L.; Friedman, Noah D.; Gahl, William A.; Glanton, Emily; Godfrey, Rena A.; Goldstein, David B.; Gould, Sarah E.; Gourdine, Jean-Philippe F.; Groden, Catherine; Gropman, Andrea; Haendel, Melissa; Hamid, Rizwan; Hanchard, Neil A.; Handley, Lori H.; Herzog, Matthew; Holm, Ingrid A.; Hom, Jason; Howerton, Ellen M.; Huang, Yong; Jacob, Howard J.; Jain, Mahim; Jiang, Yong‐Hui; Johnston, Jean M.; Jones, Angela L.; Kohane, Isaac S.; Krasnewich, Donna M.; Krieg, Elizabeth L.; Krier, Joel B.; Lalani, Seema R.; Lau, Chuen-Yen; Lazar, Jozef; Lee, Brendan; Lee, Hane; Levy, Shawn; Lewis, Richard A.; Lincoln, Sharyn A.; Lipson, Allen; Loo, Sandra K.; Loscalzo, Joseph; Maas, Richard L.; Macnamara, Ellen; MacRae, Calum A.; Maduro, Valerie V.; Majcherska, Marta M.; Malicdan, May Christine V.; Mamounas, Laura A.; Manolio, Teri A.; Markello, Thomas C.; Marom, Ronit; Martínez‐Agosto, Julian A.; Marwaha, Shruti; May, Thomas; McConkie‐Rosell, Allyn; McCormack, Colleen E.; McCray, Alexa T.; Might, Matthew; Moretti, Paolo; Morimoto, Marie; Mulvihill, John J.; Murphy, Jennifer L.; Muzny, Donna M.; Nehrebecky, Michele; Nelson, Stan F.; Newberry, J. Scott; Newman, John H.; Nicholas, Sarah K.; Novacic, Donna; Orange, Jordan S.; Pallais, J. Carl; Palmer, Christina G.S.; Papp, Jeanette C.; Parker, Neil H.; Peña, Loren; Phillips, John A.; Posey, Jennifer E.; Postlethwait, John H.; Potocki, Lorraine; Pusey, Barbara N.; Reuter, Chloe M.; Robertson, Amy K.; Rodan, Lance H.; Rosenfeld, Jill A.; Sampson, Jacinda B.; Samson, Susan L.; Schoch, Kelly; Schroeder, Molly C.; Scott, Daryl A.; Sharma, Prashant; Shashi, Vandana; Signer, Rebecca; Silverman, Edwin K.; Sinsheimer, Janet S.; Smith, Kevin S.; Spillmann, Rebecca C.; Splinter, Kimberly; Stoler, Joan M.; Stong, Nicholas; Sullivan, Jennifer; Sweetser, David A.; Tifft, Cynthia J.; Toro, Camilo; Tran, Alyssa A.; Urv, Tiina K.; Valivullah, Zaheer; Vilain, Éric; Vogel, Tiphanie P.; Wahl, Colleen E.; Walley, Nicole M.; Walsh, Christopher A.; Ward, Patricia A.; Waters, Katrina M.; Westerfield, Monte; Wise, Anastasia L.; Wolfe, Lynne A.; Worthey, Elizabeth A.; Yamamoto, Shinya; Yang, Yaping; Yu, Guoyun; Zastrow, Diane B.; Zheng, Allison

doi:10.1016/j.ajhg.2018.11.007

Cited by 61 publications

(56 citation statements)

References 73 publications

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“…The composition of the complexes varies depending on time and cell type. Mutations of BAF complex components have been associated with cancer (Hodges et al, 2019) but also brain development impairments and intellectual disability (Machol et al, 2019).…”

Section: Molecular Mechanisms Associated With the Generation And Amplmentioning

confidence: 99%

Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells

Penisson

Ladewig

Belvindrah

et al. 2019

Front. Cell. Neurosci.

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The development of the cerebral cortex relies on different types of progenitor cell. Among them, the recently described basal radial glial cell (bRG) is suggested to be of critical importance for the development of the brain in gyrencephalic species. These cells are highly numerous in primate and ferret brains, compared to lissencephalic species such as the mouse in which they are few in number. Their somata are located in basal subventricular zones in gyrencephalic brains and they generally possess a basal process extending to the pial surface. They sometimes also have an apical process directed toward the ventricular surface, similar to apical radial glial cells (aRGs) from which they are derived, and whose somata are found more apically in the ventricular zone. bRGs share similarities with aRGs in terms of gene expression ( SOX2 , PAX6 , and NESTIN ), whilst also expressing a range of more specific genes (such as HOPX ). In primate brains, bRGs can divide multiple times, self-renewing and/or generating intermediate progenitors and neurons. They display a highly specific cytokinesis behavior termed mitotic somal translocation. We focus here on recently identified molecular mechanisms associated with the generation and amplification of bRGs, including bRG-like cells in the rodent. These include signaling pathways such as the FGF-MAPK cascade, SHH, PTEN/AKT, PDGF pathways, and proteins such as INSM, GPSM2, ASPM, TRNP1, ARHGAP11B, PAX6, and HIF1α. A number of these proteins were identified through transcriptome comparisons in human aRGs vs. bRGs, and validated by modifying their activities or expression levels in the mouse. This latter experiment often revealed enhanced bRG-like cell production, even in some cases generating folds (gyri) on the surface of the mouse cortex. We compare the features of the identified cells and methods used to characterize them in each model. These important data converge to indicate pathways essential for the production and expansion of bRGs, which may help us understand cortical development in health and disease.

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Section: Molecular Mechanisms Associated With the Generation And Amplmentioning

confidence: 99%

Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells

Penisson

Ladewig

Belvindrah

et al. 2019

Front. Cell. Neurosci.

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“…We find that DIGs are enriched for genes encoding proteins associated with chromatin regulation and identify the SWI/SNF ATP-dependent chromatin remodelling complex as the most enriched DIG-associated cellular component. Currently, mutations in 12 of the 29 genes that encode subunits of the human SWI/SNF complex have been found in patients with ID (Bramswig et al, 2017; Dias et al, 2016; Kleefstra et al, 2012; Machol et al, 2019; Marom et al, 2017; Nixon et al, 2018; Rivière et al, 2012; Tsurusaki et al, 2012; Van Houdt et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Individual components of the SWI/SNF chromatin remodelling complex have distinct roles in memory neurons of theDrosophilamushroom body

Chubak

Nixon

Stone

et al. 2019

Disease Models &Amp; Mechanisms

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Technology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders such as intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodelling complex is one of the most over-represented cellular components disrupted in ID. We investigated the role of individual subunits of this large protein complex using targeted RNA interference in post-mitotic memory-forming neurons of the Drosophila mushroom body (MB). Knockdown flies were tested for defects in MB morphology, short-term memory and long-term memory. Using this approach, we identified distinct roles for individual subunits of the Drosophila SWI/SNF complex. Bap60, Snr1 and E(y)3 are required for pruning of the MBγ neurons during pupal morphogenesis, while Brm and Osa are required for survival of MBγ axons during ageing. We used the courtship conditioning assay to test the effect of MB-specific SWI/SNF knockdown on short- and long-term memory. Several subunits, including Brm, Bap60, Snr1 and E(y)3, were required in the MB for both short- and long-term memory. In contrast, Osa knockdown only reduced long-term memory. Our results suggest that individual components of the SWI/SNF complex have different roles in the regulation of structural plasticity, survival and functionality of post-mitotic MB neurons. This study highlights the many possible processes that might be disrupted in SWI/SNF-related ID disorders. Our broad phenotypic characterization provides a starting point for understanding SWI/SNF-mediated gene regulatory mechanisms that are important for development and function of post-mitotic neurons.

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“…This complex plays an essential role during neuron development and the absence of Smarcc2 in mice resulted in impaired embryonic and adult neurogenesis inducing cognitive dysfunction 45 . Mutations in this gene have already been found in patients with ASD 46 or neurodevelopmental disorder 47 , and mutations in another subunit of this complex, SMARCA2, have been reported in individuals with SZ 48,49 .…”

Section: Smarcc2 Hells Upf2mentioning

confidence: 95%

Contribution of common and rare damaging variants in familial forms of bipolar disorder and phenotypic outcome

et al. 2020

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Genome-wide association studies on bipolar disorders (BD) have revealed an additive polygenic contribution of common single-nucleotide polymorphisms (SNPs). However, these SNPs explain only 25% of the overall genetic variance and suggest a role of rare variants in BD vulnerability. Here, we combined high-throughput genotyping data and whole-exome sequencing in cohorts of individuals with BD as well as in multiplex families with a high density of affected individuals in order to determine the contribution of both common and rare variants to BD genetic vulnerability. Using polygenic risk scores (PRS), we showed a strong contribution of common polymorphisms previously associated with BD and schizophrenia (SZ) and noticed that those specifically associated with SZ contributed more in familial forms of BD than in non-familial ones. The analysis of rare damaging variants shared by affected individuals in multiplex families with BD revealed a single interaction network enriched in neuronal and developmental biological pathways, as well as in the regulation of gene expression. We identified four genes with a higher mutation rate in individuals with BD than in the general population and showed that mutations in two of them were associated with specific clinical manifestations. In addition, we showed a significant negative correlation between PRS and the number of rare damaging variants specifically in unaffected individuals of multiplex families. Altogether, our results suggest that common and rare genetic variants both contribute to the familial aggregation of BD and this genetic architecture may explain the heterogeneity of clinical manifestations in multiplex families.

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Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Cited by 61 publications

References 73 publications

Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells

Genes and Mechanisms Involved in the Generation and Amplification of Basal Radial Glial Cells

Individual components of the SWI/SNF chromatin remodelling complex have distinct roles in memory neurons of theDrosophilamushroom body

Contribution of common and rare damaging variants in familial forms of bipolar disorder and phenotypic outcome

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