A novelSMARCC1-mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus
Authors: Singh Amrita K. , Viviano Stephen , Allington Garrett , McGee Stephen , Kiziltug Emre , Mekbib Kedous Y. , Shohfi John P. , Duy Phan Q. , DeSpenza Tyrone , Furey Charuta G , Reeves Benjamin C. , Smith Hannah , Ma Shaojie , Sousa André M. M. , Cherskov Adriana , Allocco August , Nelson-Williams Carol , Haider Shozeb , Rizvi Syed R. A. , Alper Seth L. , Sestan Nenad , Shimelis Hermela , Walsh Lauren K. , Lifton Richard P. , Moreno-De-Luca Andres , Jin Sheng Chih , Kruszka Paul , Deniz Engin , Kahle Kristopher T. 
Published: March 2023

ABSTRACTImportanceHydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery. A few familial forms of congenital hydrocephalus (CH) have been identified, but the cause of most sporadic cases of CH remains elusive. Recent studies have implicatedSMARCC1, a component of theBRG1-associated factor (BAF) chromatin remodeling complex, as a candidate CH gene. However,SMARCC1variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, CH-associatedSMARCC1variants have not been functionally validated or mechanistically studiedin vivo.ObjectivesThe aims of this study are to (i) assess the extent to which rare, damagingde novomutations (DNMs) inSMARCC1are associated with cerebral ventriculomegaly; (ii) describe the clinical and radiographic phenotypes ofSMARCC1-mutated patients; and (iii) assess the pathogenicity and mechanisms of CH-associatedSMARCC1mutationsin vivo.Design, setting, and participantsA genetic association study was conducted using whole-exome sequencing from a cohort consisting of 2,697 ventriculomegalic trios, including patients with neurosurgically-treated CH, totaling 8,091 exomes collected over 5 years (2016-2021). Data were analyzed in 2023. A comparison control cohort consisted of 1,798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents sourced from the Simons simplex consortium.Main outcomes and measuresGene variants were identified and filtered using stringent, validated criteria. Enrichment tests assessed gene-level variant burden.In silicobiophysical modeling estimated the likelihood and extent of the variant impact on protein structure. The effect of a CH-associatedSMARCC1mutation on the human fetal brain transcriptome was assessed by analyzing RNA-sequencing data.Smarcc1knockdowns and a patient-specificSmarcc1variant were tested inXenopusand studied using optical coherence tomography imaging,in situhybridization, and immunofluorescence microscopy.ResultsSMARCC1surpassed genome-wide significance thresholds in DNM enrichment tests. Six rare protein-altering DNMs, including four loss-of-function mutations and one recurrent canonical splice site mutation (c.1571+1G>A) were detected in unrelated patients. DNMs localized to the highly conserved DNA-interacting SWIRM, Myb-DNA binding, Glu-rich, and Chromo domains ofSMARCC1. Patients exhibited developmental delay (DD), aqueductal stenosis, and other structural brain and heart defects. G0 and G1Smarcc1 Xenopusmutants exhibited aqueductal stenosis and cardiac defects and were rescued by human wild-typeSMARCC1but not a patient-specificSMARCC1mutant. HydrocephalicSMARCC1-mutant human fetal brain andSmarcc1-mutantXenopusbrain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factorsNEUROD2andMAB21L2.ConclusionsSMARCC1is abona fideCH risk gene. DNMs inSMARCC1cause a novel human BAFopathy we term “SMARCC1-associatedDevelopmentalDysgenesisSyndrome (SaDDS)”, characterized by 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 human CH pathogenesis. These results highlight the utility of trio-based WES for identifying risk genes for congenital structural brain disorders and suggest WES may be a valuable adjunct in the clinical management of CH patients.KEY POINTSQuestionWhat is the role ofSMARCC1, a core component of theBRG1-associated factor (BAF) chromatin remodeling complex, in brain morphogenesis and congenital hydrocephalus (CH)?FindingsSMARCC1harbored an exome-wide significant burden of rare, protein-damagingde novomutations (DNMs) (p = 5.83 × 10−9) in the largest ascertained cohort to date of patients with cerebral ventriculomegaly, including treated CH (2,697 parent-proband trios).SMARCC1contained four loss-of-function DNMs and two identical canonical splice site DNMs in a total of six unrelated patients. Patients exhibited developmental delay, aqueductal stenosis, and other structural brain and cardiac defects.Xenopus Smarcc1mutants recapitulated core human phenotypes and were rescued by the expression of human wild-type but not patient-mutantSMARCC1. HydrocephalicSMARCC1-mutant human brain andSmarcc1-mutantXenopusbrain exhibited similar alterationsin the expression of key transcription factors that regulate neural progenitor cell proliferation.MeaningSMARCC1is essential for human brain morphogenesis and is abona fideCH risk gene.SMARCC1mutations cause a novel human BAFopathy we term “SMARCC1-associatedDevelopmentalDysgenesisSyndrome (SaDDS)”. These data implicate epigenetic dysregulation of fetal neural progenitors in the pathogenesis of hydrocephalus, with diagnostic and prognostic implications for patients and caregivers.