Germline Mutation Enrichment in Pathways Controlling Endothelial Cell Homeostasis in Patients with Brain Arteriovenous Malformation: Implication for Molecular Diagnosis

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.

SMADS-Mediate Molecular Mechanisms in Sjögren’s Syndrome

“…EndMT in CCM1-ablated endothelial cells is mediated by the up-regulation of Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling, and the consequent EndMT activation results crucial in the onset and progression of CCM disease [ 19 ]. In this context, a recent study highlighted a role for EndMT in brain arteriovenous malformation disease (AVM), a congenital defect affecting brain microvasculature, demonstrating that germline mutations in several genes related to TGF-β/BMP signalling are found to contribute to EndMT in AVM [ 23 , 24 ].…”

Associated genetic variants and potential pathogenic mechanisms of brain arteriovenous malformation

“…Another candidate gene association study (online supplemental table 2)26 investigated variants that were not evaluated in two or more studies. The remaining 13 studies were case reports27–29 or case series30–39 in which exome sequencing was performed. A specific flowchart demonstrating the process of selection is presented in figure 1.…”

“…Among the remaining 14 studies used for qualitative description, there was a case-control study, three case reports, and nine case series studies (online supplemental table 2). The candidate genes that possibly contributed to the risk of bAVM development included the following: TGFR-β2, 28 ACVRL1, 29 LEMD, 30 ENG, 30 FBN2, 31 and RNF111 31 in the bone morphogenic protein (BMP)/transforming growth factor beta (TGF-β) signaling pathway; PITPNM3, 30 SARS, 30 and MYLK 32 in the vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) signaling pathway ; TAB1 31 , CAMK2B 31 and PEAK1 32 in the RAS/mitogen activated protein kinase (MAPK) signaling pathway; and HSPG2 32 and RNF213 33 in nuclear factor ĸB (NFĸB) and inflammatory signaling pathways. The functions and pathways in which EPHA2, 31 EPHB2, 31 STK4, 29 NCoR2, 31 SLIT2, 31 LRP2, 32 PIEZO1, 32 and PRUNE2 32 played a role in the process of bAVM occurrence are shown in online supplemental table 2.…”

Review of treatment and therapeutic targets in brain arteriovenous malformation

“…35 Whole exome sequencing of 5 bAVM patients identified germline mutations enriched in pathways controlling endothelial homeostasis and 2 novel pathways: cilia morphogenesis and ion homeostasis. 36 In addition, Scimone et al 37 performed whole exome sequencing to evaluate a young boy with a sporadic bAVM and detected 20 likely gene-disrupting variants affecting many genetic loci, including a de novo nonsense variant in the STK4 gene.…”