Combined exome and RNA-seq analysis in patients with rare non-syndromic inherited brain arteriovenous malformation suggests a novel function for PTPN13 in arterial specification.

Non-syndromic inherited brain arteriovenous malformation (bAVM) is a very rare condition whose molecular basis is still uncharacterized. In contrast, sporadic bAVM can arise following gain-of-function mutations in the KRAS and BRAF proto-oncogenes. The bAVM lesion is characterized by a direct arteriole-to-venule shunt and the absence of a normal capillary bed, due to impaired expression of endothelial differentiation markers and failed arterial specification. In this context, perturbation of EphrinB2-EphB4 reverse signaling plays a pivotal role. According to this knowledge, this study describes the possible role of the PTPN13 gene in non-syndromic inherited bAVM. Whole-exome sequencing was performed on germline DNA purified from peripheral blood of two consanguineous relatives affected by bAVM. Common rare genetic variants were selected and affected genes were prioritized. RNA-sequencing was conducted on endothelial cells isolated from the bAVM lesion after surgical removal. Differentially expressed genes were functionally clustered. The resulting data were integrated to determine the possible common genetic cause of the phenotype in both relatives. PTPN13 was identified as a possible causative gene for non-syndromic inherited bAVM. By dephosphorylating EphrinB2 and SRC in particular, it contributes to the modulation of the EphrinB2- EphB4 reverse signaling, during arterial specification. Moreover, this phenotype does not depend on KRAS and BRAF gain-of-function, in contrast to the sporadic form. Given the exceptional nature of the non-syndromic inherited phenotype, this study represents the first evidence of a candidate gene for this rare form of the disease, further suggesting a novel field of investigation for the bAVM pathogenesis.