Abstract

Vein of Galen malformations (VOGMs) represent the most common and most severe subtype of congenital brain arteriovenous malformations, yet the underlying genetic and developmental mechanisms remain incompletely understood. This dissertation investigates the etiology of VOGMs through an integrated genomic and transcriptomic approach, combining whole-exome sequencing of 310 proband-parent trios with single-cell transcriptomic profiling of 336,326 human cerebrovascular cells. Genetic analyses identified a genome-wide significant enrichment of de novo loss-of-function variants in RASA1, which encodes the Ras suppressor p120 RasGAP (2042.5-fold enrichment; p = 4.79 × 10⁻⁷). Rare, damaging inherited variants were significantly enriched in EPHB4 (17.5-fold; p = 1.22 × 10⁻⁵), a receptor tyrosine kinase that functions in concert with p120 RasGAP to regulate endothelial signaling and vascular development. Additional candidate genes implicated in VOGM pathogenesis include ACVRL1, NOTCH1 and PTPN11, with ACVRL1 variants also observed in a multigenerational pedigree, supporting a heritable contribution in a subset of cases. Integrative transcriptomic analyses localized VOGM-associated gene expression to endothelial cells during late gestational development, defining this population as a key spatiotemporal locus of disease pathophysiology. Functional modeling in mice demonstrated that endothelial expression of a VOGM-linked EPHB4 variant (p.Phe867Leu) disrupted developmental angiogenesis and impaired arterial-capillary-venous hierarchy, but only in the context of a “second-hit” genetic background, highlighting the interplay between genetic susceptibility and developmental context. Together, these findings elucidate a genetic and mechanistic framework for VOGM pathogenesis centered on disrupted endothelial signaling. By establishing RASA1 and EPHB4 as core contributors and revealing key molecular pathways and cellular contexts, this work provides a foundation for improved genetic diagnosis, functional studies, and potential therapeutic strategies in cerebrovascular malformations.

Committee Chair

Peter Jin

Committee Members

Amber Stratman; Cynthia Ortinau; Kristopher Kahle; Peter Jin; Ting Wang; Yang Li

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Genetics & Genomics)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

7-24-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0003-0248-0119

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Available for download on Thursday, July 23, 2026

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Biology Commons

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