# Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $475,039

## Abstract

PROJECT SUMMARY
The genetic study of severe human congenital cerebrovascular anomalies can shed insight into mechanisms of
normal vascular development and identify targets for therapeutic intervention. Vein of Galen aneurysmal
malformations (VOGMs) are the most common and severe of pediatric brain arterio-venous malformations
(AVMs). Significant gaps in our understanding of the molecular pathogenesis of VOGMs impede the
development of improved diagnostic and therapeutic measures. Locus heterogeneity and the sporadic nature
of VOGM cases have constituted fundamental obstacles to VOGM gene discovery. We recently applied whole
exome sequencing (WES) to overcome these obstacles and identified de novo and inherited gene mutations
that account for ~30% of sporadic VOGM cases (Duran et al., Neuron, 2019). These included a genome-wide
significant burden of rare, damaging mutations in EPHB4 (EphB4), a critical regulator of arterio-venous
specification also mutated in the familial AVM syndrome, capillary malformation (CM)-AVM type II (CM-AVM2).
We also discovered new mutations in other genes that function in the same Ephrin signaling interactome,
including RASA1 (also mutated in CM-AVM1). We further demonstrated that EphB4 exists in a physical
complex with RASA1, and have now solved the first multi-domain crystal structure of RASA1. Nonetheless,
most VOGM cases remain genetically unsolved, and the molecular mechanisms of VOGM-associated
mutations are poorly understood. To address these knowledge gaps, we propose a functional genomics
approach to discover and mechanistically elucidate VOGM-associated mutations with atomic-level resolution.
We hypothesize WES will identify novel VOGM genes and mutations, including mosaic and somatic
“second-hit” mutations, which disrupt the regulated activity of an EphB4-RASA1 signaling complex
essential for arterio-venous development. Based on our successful experience in identifying structural brain
disorder genes over the past several years, Aim 1 will ascertain additional VOGM case-parent trios and
perform WES on our growing cohort (already the largest in the world) to discover novel de novo and
transmitted germline VOGM gene mutations, mosaic variants, and somatic mutations in lesional tissue. In Aim
2, we will determine the structural and functional impact of VOGM mutations using biochemical, biophysical,
structural biology and cell biology techniques, with validation experiments in autopsied VOGM tissue, and in
skin biopsies of VOGM patients with associated cutaneous vascular malformations. Successful completion of
these Aims will increase our understanding of human cerebrovascular development and VOGM
pathophysiology. These advances will improve disease management and genetic counseling, and will
stimulate development of targeted therapeutics for VOGMs that may be broadly relevant for other vascular
lesions, including AVMs and intracranial aneurysms.

## Key facts

- **NIH application ID:** 10033009
- **Project number:** 1R01NS117609-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Titus Jonathon Boggon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,039
- **Award type:** 1
- **Project period:** 2020-07-15 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10033009

## Citation

> US National Institutes of Health, RePORTER application 10033009, Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation (1R01NS117609-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10033009. Licensed CC0.

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