Somatic Platelet Derived Growth Factor Receptor Beta Activating Variants in Fusiform Cerebral Aneurysms

Abstract

Abstract INTRODUCTION The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-yr-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of unrevealing genetic evaluations for known connective-tissue disorders, and served as a somatic mosaic for discovery of novel mutations involved in aneurysm pathogenesis. METHODS Deoxyribonucleic acid (DNA) was extracted from multiple vascular and perivascular tissue samples obtained during surgery on the index patient. Initial variant discovery was carried out via paired-sample exome sequencing between blood and diseased area fibroblasts. A single novel variant was discovered in the platelet derived growth factor receptor beta (PDGFRB), and mutations in this gene were tested in exome sequencing of aneurysm walls from 6 patients with fusiform intracranial aneurysm and 38 patients with saccular aneurysm. RESULTS Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T > C [GRCh37/hg19]; c.1685A > G) change within PDGFRB, a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting postzygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, P < .001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive autophosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated nonligand-dependent autophosphorylation, responsive to the kinase inhibitor sunitinib. CONCLUSION Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors.