A novel SMARCC1 -mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus.

What is the role of , a core component of the B RG1- a ssociated factor (BAF) chromatin remodeling complex, in brain morphogenesis and congenital hydrocephalus (CH)? harbored an exome-wide significant burden of rare, protein-damaging mutations (DNMs) (p = 5.83 × 10 ) in the largest ascertained cohort to date of patients with cerebral ventriculomegaly, including treated CH (2,697 parent-proband trios). contained 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. mutants recapitulated core human phenotypes and were rescued by the expression of human wild-type but not patient-mutant . Hydrocephalic -mutant human brain and -mutant brain exhibited similar alterationsin the expression of key transcription factors that regulate neural progenitor cell proliferation. is essential for human brain morphogenesis and is a CH risk gene. mutations cause a novel human BAFopathy we term " S MARCC1- a ssociated D evelopmental D ysgenesis S yndrome (SaDDS)". These data implicate epigenetic dysregulation of fetal neural progenitors in the pathogenesis of hydrocephalus, with diagnostic and prognostic implications for patients and caregivers.