Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10–18/100,000. BAVM is the leading etiology of intracranial hemorrhage in children. To identify gene variants potentially contributing to disease, we sequenced the DNA of 100 families with a BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model.
We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, ENG, and three damaging variants in novel candidate genes: PITPNM3, SARS, and LEMD3, which we then functionally validated in zebrafish. Our study highlights the specific role of BMP/TGF-β and VEGF/VEGFR signaling in the etiology of BAVM. (By Sen Zhao, https://jmg.bmj.com/content/early/2018/08/17/jmedgenet-2017-105224 )