Date of Award

January 2023

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Engin Deniz

Abstract

Congenital hydrocephalus (CH) is a common disorder requiring neurosurgery in children, however its pathogenesis is poorly understood. Recent studies have implicated SMARCC1 as a candidate CH gene but variants have not been conclusively linked with a human syndrome, nor functionally validated in vivo. This study aims to (i) assess the extent of CH risk associated with SMARCC1 variants; (ii) describe associated clinical and radiographic phenotypes; and (iii) assess the pathogenicity and mechanisms of SMARCC1 depletion in a novel animal model of CH. A genetic association study was conducted using whole-exome sequencing from a CH discovery cohort consisting of 492 neurosurgically-treated probands. Exomes from a genetic referral laboratory cohort and a large healthcare-based cohort were analyzed to distinguish risk variants from variants of unknown significance and identify rare, large-effect recurrent variants. In silico biophysical modeling estimated the likelihood and extent of variant impact on protein structure. The effect of a CH-associated de novo SMARCC1 mutation on the human fetal brain transcriptome was assessed by analyzing RNA-sequencing data. Smarcc1 knockdowns were generated in Xenopus tropicalis and studied using optical coherence tomography imaging, in situ hybridization, and immunofluorescence microscopy. SMARCC1 surpassed genome-wide significance thresholds in the discovery cohort and yielded 11 total rare de novo, unphased, or transmitted SMARCC1 variants localized to highly conserved domains, including seven loss-of-function (LoF) variants. 10/11 patients had treated obstructive hydrocephalus with aqueductal stenosis. Associated corpus callosum abnormalities, septal agenesis, developmental delay, and cardiac defects were common. Replication cohorts identified four recurrent variants. G0 and G1 Smarcc1 Xenopus mutants recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Both SMARCC1-variant human fetal brain and Smarcc1-depleted Xenopus brain exhibited altered expression of genes linked to midgestational neurogenesis, including NEUROD2 and MAB21L2. SMARCC1 is a bona fide CH risk gene, associated with novel human BAFopathy we term “SMARCC1-associated Developmental Dysgenesis Syndrome (SaDDS)” characterized by ventriculomegaly or hydrocephalus with a variety of structural defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodeling complex for human brain development and further support a neural stem cell paradigm of human CH pathogenesis.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 07/24/2025

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