Importance: Hydrocephalus, 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 implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodeling complex, as a candidate 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. Objectives: The aims of this study are to (i) assess the extent to which rare, damaging de novo mutations (DNMs) in SMARCC1 are associated with cerebral ventriculomegaly; (ii) describe the clinical and radiographic phenotypes of SMARCC1-mutated patients; and (iii) assess the pathogenicity and mechanisms of CH-associated SMARCC1 mutations in vivo. Design, setting, and participants: A 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 measures: Gene variants were identified and filtered using stringent, validated criteria. Enrichment tests assessed gene-level variant burden. In silico biophysical modeling estimated the likelihood and extent of the variant impact on protein structure. The effect of a CH-associated SMARCC1 mutation on the human fetal brain transcriptome was assessed by analyzing RNA-sequencing data. Smarcc1 knockdowns and a patient-specific Smarcc1 variant were tested in Xenopus and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence microscopy. Results: SMARCC1 surpassed 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 of SMARCC1. Patients exhibited developmental delay (DD), aqueductal stenosis, and other structural brain and heart defects. G0 and G1 Smarcc1 Xenopus mutants exhibited aqueductal stenosis and cardiac defects and were rescued by human wild-type SMARCC1 but not a patient-specific SMARCC1 mutant. Hydrocephalic SMARCC1-mutant human fetal brain and Smarcc1-mutant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. Conclusions: SMARCC1 is a bona fide CH risk gene. DNMs in SMARCC1 cause a novel human BAFopathy we term SMARCC1-associated Developmental Dysgenesis Syndrome (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.

S. McGee and P. Kruszka are employees of GeneDx. All other co-authors have no conflicts of interest to disclose.

This work was supported by the Yale-NIH Center for Mendelian Genomics (grant 5U54HG006504) and the University of Washington Center for Mendelian Genomics (grants UW-CMG, UM1HG006493, U24HG008956), National Institutes of Health (grants R01 NS111029-01A1, R01 NS109358, R01 NS127879-01, R01HL109942, R21 NS116484-02, and K12 228168) (K.K., E.D, S.C.J); the Rudi Schulte Research Institute (K.K.), the National Heart, Lung, and Blood Institute (R00HL143036-02) (S.C.J), the Hydrocephalus Association Innovator Award (E.D., K.K., S.C.J.), the Clinical and Translational Research Funding Program Award (CTSA1405; (S.C.J.), the Childrens Discovery Institute Faculty Scholar Award (CDI-FR-2021-926) (S.C.J), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (R01HD104938-01A1) (A.M.D).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Human Investigation Committee of Yale University gave ethical approval for this work. The Human Research Protection Program of Massachusetts General Hospital gave ethical approval for this work. The Western Institutional Review Board of Western Institutional Review Board Inc. gave ethical approval for this work.

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All data produced in the present study will be made available upon reasonable request from Dr. Kahle at kahle.kristopher@mgh.harvard.edu.