CM AVM and VOGM are thought
CM-AVM and VOGM are thought to be two distinct disorders, with CM-AVM characterized by atypical CMs, with or without AVM in variable body parts, while VOGM is a type of cerebral AVM . The fact that VOGM is infrequently reported as the AVM in CM-AVM patients, and CMs are quite often identified in patients with VOGM and their unaffected family members carrying the disease-causing mutation, raises the question whether there is a shared genetic mechanism underlying these two diseases. Additionally, even though it is very difficult to estimate whether there is an enrichment of ephrinB2-EphB4-RASA1 mutations in cerebrovascular diseases compared with other vascular malformations, given the incompleteness of the publicly available phenotype data, the fact that the ephrin receptor signaling pathway was identified as the only over-represented pathway in VOGM cases but not controls  provided strong evidence of a role for ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development. Moreover, other than cardiac defects, cerebral manifestation is the most commonly described defect in animal models of ephrinB2 2, 20, 25, EphB4 , and RASA1 . Future studies, with thorough history and physical examinations, are needed to better understand the phenotypical overlap of different cerebrovascular disorders as well as understand the overlap between cerebral and other vascular defects in humans. The results of these studies will in turn aid genetic studies into the investigation of their shared mechanisms and the prevalence of risk genes. The reason why one mutation can have such a large spectrum of manifestation is not yet completely clear. Two mechanisms can potentially explain some of the cases. First, some cases could have a somatic second-hit during development, which would explain the localized nature and multifocality of the lesions, as well as the variable phenotype within OTX-015 . Somatic mosaicism has been verified in several vascular malformations 65, 66, including CM-AVM 30, 46. The second mechanism could involve genetic modifiers that may interact and alter the expressivity of the disease-causing gene , or it could be that more than one gene with one defective allele (trans-compound heterozygote) is needed for disease manifestation . Future studies with large trio-based cohorts and collection of tissue samples are needed to test these hypotheses. Despite the large number of CM-AVM cases explained by RASA1 mutations, genetic causes for many patients remain unknown. As most of the published studies performed target resequencing on candidate genes, some additional cases may be explained if they were screened for genes that have been identified recently, such as EPHB4 and EFNB2. Additionally, target sequencing limites the possibility of identifying novel disease-associated genes. More unbiased genome-wide sequencing studies are needed to identify novel genes and better understand the genetic underpinnings of the disease. Furthermore, mutations in the regulatory and intronic regions of the known disease-associated genes have not yet been examined. Future studies using whole genome sequencing could potentially unveil the contribution of noncoding variants in known genes and even identify novel mutations in noncoding regions. Genetic findings in ephrinB2-EphB4-RASA1 signaling axis genes also provided insights into potential diagnostic and therapeutic strategies for cerebrovascular disorders. Given the incomplete penetrance and variable expressivity, prenatal genetic screens in pregnant women with a family history of cutaneous vascular lesions and/or other vascular malformations could help the early diagnosis and treatment design of the disease. Interestingly, the phenotype in efnb2a-ephb4a and rasa1a knockdown zebrafish could be rescued by chemical inhibitors of PI3K-TORC1, indicating that reduced ephrinB2-EphB4-RASA1 expression may cause excessive PI3K/mTORC1 pathway activity, which has also been observed in surgical tissue samples from patients with vascular anomalies associated with RASA1 mutations . This suggests that targeting PI3K-TORC1 signaling might be a viable therapeutic approach for cerebrovascular diseases associated with ephrinB2-EphB4-RASA1 mutations.