The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

Abstract

Vascular anomalies (VAs) are morphogenesis defects of the vascular system (arteries, capillaries, veins, lymphatic vessels) singularly or in complex combinations, sometimes with a severe impact on the quality of life. The progress made in recent years with the identification of the key molecular pathways (PI3K/AKT/mTOR and RAS/BRAF/MAPK/ERK) and the gene mutations that lead to the appearance of VAs has allowed the deciphering of their complex genetic architecture. Understanding these mechanisms is critical both for the correct definition of the phenotype and classification of VAs, as well as for the initiation of an optimal therapy and the development of new targeted therapies. The purpose of this review is to present in synthesis the current data related to the genetic factors involved in the etiology of VAs, as well as the possible directions for future research. We analyzed the data from the literature related to VAs, using databases (Google Scholar, PubMed, MEDLINE, OMIM, MedGen, Orphanet) and ClinicalTrials.gov. The obtained results revealed that the phenotypic variability of VAs is correlated with genetic heterogeneity. The identification of new genetic factors and the molecular mechanisms in which they intervene, will allow the development of modern therapies that act targeted as a personalized therapy. We emphasize the importance of the geneticist in the diagnosis and treatment of VAs, as part of a multidisciplinary team involved in the management of VAs.

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“…As the EPHB4 G951fs variant showed normal cell proliferation, we next looked at levels of mitogen activated protein kinase (MAPK) signaling, as this major cellular growth pathway is ectopically activated in a number of vascular and lymphatic anomalies (reviewed in Reference 32). Treatment with MAPK inhibitors is clinically used for lymphatic and vascular anomalies 33–37 .…”

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“…Furthermore, gene mutations may interfere with the VEGF A signaling pathway ( 32 , 33 ). VEGF receptor-2 is the receptor for VEGF A, and some patients with IH have VEGFR2 mutations ( 34 , 35 ).…”

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“…De novo dominant heterozygous variants can also cause VAs, as outlined in Ustaszewski et al (2021). Sporadic VAs are caused by somatic mosaic variants and can be present at very low variant allele frequencies (VAFs) (<5%) in lesional tissue (Butnariu et al, 2022). In some cases, a germline predisposing variant is present, with one or more subsequent somatic variants arising within the affected lesion tissue (Ren et al, 2021).…”