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

• Published in: International journal of molecular sciences Vol. 21; no. 12; p. 4321
• Main Authors: Scimone, Concetta, Granata, Francesca, Longo, Marcello, Mormina, Enricomaria, Turiaco, Cristina, Caragliano, Antonio A, Donato, Luigi, Sidoti, Antonina, D'Angelo, Rosalia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 17.06.2020; MDPI
• Subjects: Annotations; Arterioles; brain arteriovenous malformations; Cell adhesion & migration; Cilia; Computational Biology - methods; Congenital defects; Deoxyribonucleic acid; Diagnosis; DNA; DNA sequencing; Endothelial cells; Endothelial Cells - metabolism; endothelial properties; exome sequencing; Gene Ontology; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genotypes; Germ-Line Mutation; Growth factors; Heterogeneity; Homeostasis; Humans; Intracranial Arteriovenous Malformations - diagnosis; Intracranial Arteriovenous Malformations - genetics; Kinases; Microvasculature; molecular diagnosis; Morphogenesis; Mutation; Ontology; Peripheral blood; Phenotypes; Proteins; Recidivism; Reproducibility of Results; Sequence Analysis, DNA; Signal Transduction; Transforming growth factor-b; Tumor necrosis factor-TNF; Whole Exome Sequencing; brain arteriovenous malformations; exome sequencing; endothelial properties; molecular diagnosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21124321

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.