Date of Award

January 2021

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Kristopher T. Kahle


Congenital Hydrocephalus (CH) affects 1/1000 live births and costs the US healthcare system over $2 billion annually. Mainstay therapies, hinging on surgical cerebrospinal fluid diversion, exhibit high failure rates and substantial morbidity. Limited understanding of pathogenesis warrants identification of crucial genetic drivers underlying CH and their impact on brain development. This pioneering study integrates gene discovery from the largest whole-exome sequenced CH cohort with transcriptional networks (modules) and cell-type markers from the latest transcriptomic atlases of the mid-gestational human brain to uncover the genomic and molecular architecture of CH. Exome analysis of 381 radiographically-confirmed, neurosurgically-treated sporadic CH probands (including 232 case-parent trios) identified genes with rare de novo or transmitted mutations conferring disease risk. Transcriptome analyses identified mid-gestational brain modules and cell-types enriched for cohort-determined CH risk genes, known genes previously implicated in isolated and syndromic forms of CH, and risk genes of Autism Spectrum Disorder (ASD) and Developmental Disorder (DD). Genetic drivers of CH converge in a neurodevelopmental network and in early neurogenic cell-types, implicating genetic disruption of early brain development as a primary patho-mechanism for a significant subset of CH patients. Genetic and transcriptional overlap with ASD and DD may explain persistence of these conditions in CH patients despite surgical intervention, while greater potency of CH-enriched neural precursors may account for increased frequency of structural brain abnormalities in CH than in ASD or DD alone.


This is an Open Access Thesis.

Open Access

This Article is Open Access