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Abstract
Brain arteriovenous malformation (bAVM) is a congenital defect affecting brain microvasculature, characterized by a direct shunt from arterioles to venules. Germline mutations in several genes related to transforming growth factor beta (TGF-β)/BMP signaling are linked to both sporadic and hereditary phenotypes. However, the low incidence of inherited cases makes the genetic bases of the disease unclear. To increase this knowledge, we performed a whole exome sequencing on five patients, on DNA purified by peripheral blood. Variants were filtered based on frequency and functional class. Those selected were validated by Sanger sequencing. Genes carrying selected variants were prioritized to relate these genes with those already known to be linked to bAVM development. Most of the prioritized genes showed a correlation with the TGF-βNotch signaling and vessel morphogenesis. However, two novel pathways related to cilia morphogenesis and ion homeostasis were enriched in mutated genes. These results suggest novel insights on sporadic bAVM onset and confirm its genetic heterogeneity. The high frequency of germline variants in genes related to TGF-β signaling allows us to hypothesize bAVM as a complex trait resulting from the co-existence of low-penetrance loci. Deeper knowledge on bAVM genetics can improve personalized diagnosis and can be helpful with genotype–phenotype correlations.
Highlights
Brain arteriovenous malformations are vascular malformations affecting brain vasculature
The sporadic nature of the disease can be considered a result of numerous single nucleotide polymorphisms (SNPs) in genes involved in vasculogenesis and early angiogenesis pathways, as, for instance, in vascular endothelial growth factor (VEGF) and Notch signaling [8]
As knowledge on Brain arteriovenous malformation (bAVM) is still very elusive, we recruited a group of patients affected by sporadic bAVM and performed whole exome sequencing (WES) analysis
Summary
Brain arteriovenous malformations (bAVM, OMIM #108010) are vascular malformations affecting brain vasculature. The mix of arterial and venous circulations within these lesions leads to a deficit in cerebral tissue oxygenation This complex condition usually results in major clinical manifestations such as intracerebral hemorrhage and epileptic seizures, appearing in almost 50% of patients. Disease incidence is about 0.01% worldwide and usually arises at an early age [2] It most often occurs as a sporadic condition and only a few dozen cases are reported as inherited with an autosomal dominant pattern. The sporadic nature of the disease can be considered a result of numerous single nucleotide polymorphisms (SNPs) in genes involved in vasculogenesis and early angiogenesis pathways, as, for instance, in vascular endothelial growth factor (VEGF) and Notch signaling [8]. We clustered genes carrying the detected mutations, highlighting pathways and prioritizing genes mainly linked to bAVM development
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