# Molecular and cellular characterization of congenital hydrocephalus

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $666,728

## Abstract

PROJECT SUMMARY/ABSTRACT
Congenital hydrocephalus (CH) is the leading cause for brain surgery and is associated with marked
neurodevelopmental disability. CH is traditionally considered a primary disorder of cerebrospinal fluid (CSF)
homeostasis and thereby treated with surgical CSF shunting or endoscopic third ventriculostomy procedures to
reduce CSF accumulation. One glaring concern is that ventriculomegaly often persists even after surgical
intervention, and shunting does not consistently improve neurodevelopmental outcomes in many CH patients.
While extensive research has identified new CH risk genes and highlighted their convergence in embryonic
neuroepithelial stem cells, the causes of approximately 80% of CH cases remain unknown. This is partly due to
genetic heterogeneity, reduced penetrance, and small sample sizes. Of note, non-European populations have
been significantly underrepresented in existing genetic studies. Moreover, the impact of non-coding variants,
structural variants, and somatic variants on CH mechanism remains largely uncharacterized. Additionally, the
significant clinical variability observed among different subtypes of hydrocephalus has not been thoroughly
evaluated at the molecular, cellular, and neuroimaging levels. Therefore, our objective is to establish a large
and diverse cohort of primary CH patients, with a particular focus on non-European populations. Leveraging
our expertise in genomics, neuroscience, neuroimaging, and pediatric neurology, we will enhance patient
recruitment, generate and harmonize genomic and clinical data, and use WashU’s Central Neuroimaging Data
Archive to automate quality control and image processing. This will create the largest CH cohort to date with
whole-exome sequencing (WES; n = 2,879 [2,697 trios]) and whole-genome sequencing (WGS; n = 1,020 [648
trios]) data linked with comprehensive phenotypic and neuroimaging information to identify any remaining
germline variants associated with CH. We will also perform integrative analyses of WES, WGS, transcriptomic
data, and protein-protein interaction networks to uncover additional CH risk genes, pathways, and disease-
associated cell types. To characterize somatic variants, we will conduct 500X WES on unaffected and affected
brain tissues from approximately 100 patients and study their effects on gene expression and transcript
splicing using bulk RNA-sequencing. Furthermore, to enhance diagnostic accuracy and establish a clinical and
neuroimaging signature for CH, we will reevaluate neuroimaging, clinical, and genomic data and analyze
genotype-phenotype correlations in patients with pathogenic or likely pathogenic (P/LP) variants in known and
candidate genes associated with CH. To investigate factors influencing clinical variability, we will compare
patients with CH and P/LP variants to controls without CH but with P/LP variants in the same genes. To
facilitate data sharing, visualization, and analysis, we will establish the HYDRO-Seq Geno...

## Key facts

- **NIH application ID:** 10881521
- **Project number:** 1R01NS131610-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sheng Chih Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,728
- **Award type:** 1
- **Project period:** 2024-09-01 → 2030-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881521

## Citation

> US National Institutes of Health, RePORTER application 10881521, Molecular and cellular characterization of congenital hydrocephalus (1R01NS131610-01A1). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10881521. Licensed CC0.

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