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Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation – the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.

Summary Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain’s deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Background Violent injury is the second most common cause of death among 15- to 24-year olds in the US. Up to 58% of violently injured youth return to the hospital with a second violent injury. Hospital-based violence intervention programs (HVIPs) have been shown to reduce injury recidivism through intensive case management. However, no validated guidelines for risk assessment strategies in the HVIP setting have been reported. We aimed to use qualitative methods to investigate the key components of risk assessments employed by HVIP case managers and to propose a risk assessment model based on this qualitative analysis. Materials and methods An established academic hospital-affiliated HVIP served as the nexus for this research. Thematic saturation was reached with 11 semi-structured interviews and two focus groups conducted with HVIP case managers and key informants identified through snowball sampling. Interactions were analyzed by a four-member team using Nvivo 10, employing the constant comparison method. Risk factors identified were used to create a set of models presented in two follow-up HVIP case managers and leadership focus groups. Results Eighteen key themes within seven domains (environment, identity, mental health, behavior, conflict, indicators of lower risk, and case management) and 141 potential risk factors for use in the risk assessment framework were identified. The most salient factors were incorporated into eight models that were presented to the HVIP case managers. A 29-item algorithmic structured professional judgment model was chosen. Conclusions We identified four tiers of risk factors for violent reinjury that were incorporated into a proposed risk assessment instrument, VRRAI.