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A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.
Singh AK
,
Allington G
,
Viviano S
,
McGee S
,
Kiziltug E
,
Ma S
,
Zhao S
,
Mekbib KY
,
Shohfi JP
,
Duy PQ
,
DeSpenza T
,
Furey CG
,
Reeves BC
,
Smith H
,
Sousa AMM
,
Cherskov A
,
Allocco A
,
Nelson-Williams C
,
Haider S
,
Rizvi SRA
,
Alper SL
,
Sestan N
,
Shimelis H
,
Walsh LK
,
Lifton RP
,
Moreno-De-Luca A
,
Jin SC
,
Kruszka P
,
Deniz E
,
Kahle KT
.
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Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodeling complex, as a candidate congenital hydrocephalus (CH) gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, CH-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of CH. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2,697 total ventriculomegalic trios, including patients with neurosurgically-treated CH, that total 8,091 exomes collected over 7 years (2016-2023). A comparison control cohort consisted of 1,798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons simplex consortium. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare protein-altering de novo variants (DNVs) localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest DNVs in SMARCC1 cause a novel human BAFopathy we term "SMARCC1-associated Developmental Dysgenesis Syndrome (SaDDS)", characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, DD, and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodeling complex for human brain morphogenesis and provide evidence for a "neural stem cell" paradigm of CH pathogenesis. These results highlight utility of trio-based WES for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest WES may be a valuable adjunct in clinical management of CH patients.
Alexa,
Improved scoring of functional groups from gene expression data by decorrelating GO graph structure.
2006, Pubmed
Alexa,
Improved scoring of functional groups from gene expression data by decorrelating GO graph structure.
2006,
Pubmed
Alfert,
The BAF complex in development and disease.
2019,
Pubmed
Al Mutairi,
A mendelian form of neural tube defect caused by a de novo null variant in SMARCC1 in an identical twin.
2018,
Pubmed
Barish,
BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms.
2020,
Pubmed
Bevilacqua,
SWI/SNF chromatin-remodeling complexes in cardiovascular development and disease.
2014,
Pubmed
Bhattacharya,
CRISPR/Cas9: An inexpensive, efficient loss of function tool to screen human disease genes in Xenopus.
2015,
Pubmed
,
Xenbase
Bögershausen,
Mutational Landscapes and Phenotypic Spectrum of SWI/SNF-Related Intellectual Disability Disorders.
2018,
Pubmed
Brugmans,
A Carboxy-terminal Smarcb1 Point Mutation Induces Hydrocephalus Formation and Affects AP-1 and Neuronal Signalling Pathways in Mice.
2023,
Pubmed
Cao,
The single-cell transcriptional landscape of mammalian organogenesis.
2019,
Pubmed
Cao,
Camk2a-Cre-mediated conditional deletion of chromatin remodeler Brg1 causes perinatal hydrocephalus.
2015,
Pubmed
Cappuccio,
De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.
2020,
Pubmed
Chandler,
The SWI/SNF BAF-A complex is essential for neural crest development.
2016,
Pubmed
Chen,
Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.
2022,
Pubmed
Cinalli,
Hydrocephalus in aqueductal stenosis.
2011,
Pubmed
Clapier,
Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes.
2017,
Pubmed
Clapier,
The biology of chromatin remodeling complexes.
2009,
Pubmed
Da,
Structure and function of the SWIRM domain, a conserved protein module found in chromatin regulatory complexes.
2006,
Pubmed
Date,
Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus.
2019,
Pubmed
,
Xenbase
DelBove,
Identification of a core member of the SWI/SNF complex, BAF155/SMARCC1, as a human tumor suppressor gene.
2011,
Pubmed
Deniz,
CRISPR/Cas9 F0 Screening of Congenital Heart Disease Genes in Xenopus tropicalis.
2018,
Pubmed
,
Xenbase
Deniz,
Xenopus Tadpole Craniocardiac Imaging Using Optical Coherence Tomography.
2022,
Pubmed
,
Xenbase
DeSpenza,
PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets.
2021,
Pubmed
D'Gama,
Somatic mosaicism and neurodevelopmental disease.
2018,
Pubmed
Diab,
Analysis workflow to assess de novo genetic variants from human whole-exome sequencing.
2021,
Pubmed
Diets,
A recurrent de novo missense pathogenic variant in SMARCB1 causes severe intellectual disability and choroid plexus hyperplasia with resultant hydrocephalus.
2019,
Pubmed
Dong,
Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies.
2015,
Pubmed
Dur,
In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces.
2020,
Pubmed
,
Xenbase
Duran,
Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation.
2019,
Pubmed
Duy,
Brain ventricles as windows into brain development and disease.
2022,
Pubmed
Duy,
A neural stem cell paradigm of pediatric hydrocephalus.
2023,
Pubmed
Duy,
Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus.
2022,
Pubmed
Encha-Razavi,
Features of the developing brain.
2003,
Pubmed
Etchegaray,
Prenatal genetic considerations in congenital ventriculomegaly and hydrocephalus.
2020,
Pubmed
Furey,
De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus.
2018,
Pubmed
Govaert,
How idiopathic is idiopathic external hydrocephalus?
1991,
Pubmed
Hao,
Integrated analysis of multimodal single-cell data.
2021,
Pubmed
Harmacek,
A unique missense allele of BAF155, a core BAF chromatin remodeling complex protein, causes neural tube closure defects in mice.
2014,
Pubmed
Henrique,
Expression of a Delta homologue in prospective neurons in the chick.
1995,
Pubmed
,
Xenbase
Ho,
An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network.
2009,
Pubmed
Ho,
An embryonic stem cell chromatin remodeling complex, esBAF, is essential for embryonic stem cell self-renewal and pluripotency.
2009,
Pubmed
,
Xenbase
Homsy,
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.
2015,
Pubmed
Hoyer,
Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability.
2012,
Pubmed
Jellinger,
Anatomopathology of non-tumoral aqueductal stenosis.
1986,
Pubmed
Jin,
Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus.
2020,
Pubmed
Jin,
Inference and analysis of cell-cell communication using CellChat.
2021,
Pubmed
Kadoch,
Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy.
2013,
Pubmed
Kang,
Spatio-temporal transcriptome of the human brain.
2011,
Pubmed
Kaplanis,
Evidence for 28 genetic disorders discovered by combining healthcare and research data.
2020,
Pubmed
Karczewski,
The mutational constraint spectrum quantified from variation in 141,456 humans.
2020,
Pubmed
Kaufman,
The genetic basis of non-syndromic intellectual disability: a review.
2010,
Pubmed
Kenneth,
SWI/SNF regulates the cellular response to hypoxia.
2009,
Pubmed
Kent,
The human genome browser at UCSC.
2002,
Pubmed
Kim,
Srg3, a mouse homolog of yeast SWI3, is essential for early embryogenesis and involved in brain development.
2001,
Pubmed
Kosmicki,
Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.
2017,
Pubmed
Krumm,
Excess of rare, inherited truncating mutations in autism.
2015,
Pubmed
Kundishora,
Genomics of human congenital hydrocephalus.
2021,
Pubmed
Lane,
Obtaining Xenopus tropicalis Eggs.
2022,
Pubmed
,
Xenbase
Lee,
Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein.
1995,
Pubmed
,
Xenbase
Lefebvre,
Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations.
2021,
Pubmed
Lei,
SWI/SNF in cardiac progenitor cell differentiation.
2013,
Pubmed
Li,
Integrative functional genomic analysis of human brain development and neuropsychiatric risks.
2018,
Pubmed
Machol,
Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.
2019,
Pubmed
Manichaikul,
Robust relationship inference in genome-wide association studies.
2010,
Pubmed
Mari,
Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability.
2015,
Pubmed
Masliah-Planchon,
SWI/SNF chromatin remodeling and human malignancies.
2015,
Pubmed
McKenna,
The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
2010,
Pubmed
Mehrotra,
SWI/SNF chromatin remodeling enzymes are associated with cardiac hypertrophy in a genetic rat model of hypertension.
2013,
Pubmed
Miller,
Transcriptional landscape of the prenatal human brain.
2014,
Pubmed
Morrison,
Chromatin-remodeling links metabolic signaling to gene expression.
2020,
Pubmed
Narayanan,
Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development.
2015,
Pubmed
Narayanan,
Chromatin Remodeling BAF155 Subunit Regulates the Genesis of Basal Progenitors in Developing Cortex.
2018,
Pubmed
Nguyen,
Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development.
2016,
Pubmed
Ninkovic,
The BAF complex interacts with Pax6 in adult neural progenitors to establish a neurogenic cross-regulatory transcriptional network.
2013,
Pubmed
Nowakowski,
Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex.
2017,
Pubmed
Olson,
NeuroD2 is necessary for development and survival of central nervous system neurons.
2001,
Pubmed
Panamarova,
The BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo.
2016,
Pubmed
Purcell,
PLINK: a tool set for whole-genome association and population-based linkage analyses.
2007,
Pubmed
Reuter,
The Cardiac Genome Clinic: implementing genome sequencing in pediatric heart disease.
2020,
Pubmed
Ritchie,
limma powers differential expression analyses for RNA-sequencing and microarray studies.
2015,
Pubmed
Rive Le Gouard,
First reports of fetal SMARCC1 related hydrocephalus.
2023,
Pubmed
Rodríguez,
Neural Stem Cells and Fetal-Onset Hydrocephalus.
2017,
Pubmed
Rodríguez,
A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus.
2012,
Pubmed
Ronan,
From neural development to cognition: unexpected roles for chromatin.
2013,
Pubmed
Santen,
Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome.
2012,
Pubmed
Santen,
Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients.
2013,
Pubmed
Seo,
The SWI/SNF chromatin remodeling protein Brg1 is required for vertebrate neurogenesis and mediates transactivation of Ngn and NeuroD.
2005,
Pubmed
,
Xenbase
Slavotinek,
Prenatal presentation of multiple anomalies associated with haploinsufficiency for ARID1A.
2022,
Pubmed
Sokpor,
Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders.
2017,
Pubmed
Son,
The role of BAF (mSWI/SNF) complexes in mammalian neural development.
2014,
Pubmed
Sousa,
Nicolaides-Baraitser syndrome: Delineation of the phenotype.
2009,
Pubmed
Stram,
Software for tag single nucleotide polymorphism selection.
2005,
Pubmed
Takashima,
[Pathology of congenital aqueductal stenosis and posthemorrhagic hydrocephalus].
1994,
Pubmed
Tully,
Infantile hydrocephalus: a review of epidemiology, classification and causes.
2014,
Pubmed
Tuoc,
Chromatin regulation by BAF170 controls cerebral cortical size and thickness.
2013,
Pubmed
Van der Auwera,
From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.
2013,
Pubmed
Van Houdt,
Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.
2012,
Pubmed
Vieira,
BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease.
2017,
Pubmed
Wang,
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data.
2010,
Pubmed
Wang,
Diversity and specialization of mammalian SWI/SNF complexes.
1996,
Pubmed
Wang,
Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy.
2022,
Pubmed
Wei,
A Bayesian framework for de novo mutation calling in parents-offspring trios.
2015,
Pubmed
Wieczorek,
A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling.
2013,
Pubmed
Wiley,
SWI/SNF chromatin-remodeling enzymes Brahma-related gene 1 (BRG1) and Brahma (BRM) are dispensable in multiple models of postnatal angiogenesis but are required for vascular integrity in infant mice.
2015,
Pubmed
Wilfert,
Recent ultra-rare inherited variants implicate new autism candidate risk genes.
2021,
Pubmed
Wong,
Developmental expression of Mab21l2 during mouse embryogenesis.
1999,
Pubmed
Wullimann,
Secondary neurogenesis in the brain of the African clawed frog, Xenopus laevis, as revealed by PCNA, Delta-1, Neurogenin-related-1, and NeuroD expression.
2005,
Pubmed
,
Xenbase
Yan,
Structural Insights into BAF47 and BAF155 Complex Formation.
2017,
Pubmed
Yan,
BAF250B-associated SWI/SNF chromatin-remodeling complex is required to maintain undifferentiated mouse embryonic stem cells.
2008,
Pubmed
Yao,
Epigenetic mechanisms in neurogenesis.
2016,
Pubmed
Zhao,
Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling.
1998,
Pubmed
