Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

Yigit Karasozen, Joshua W. Osbun, Carolina Angelica Parada, Tina Busald, Philip Tatman, Luis F. Gonzalez-Cuyar, Christopher J. Hale, Diana Alcantara, Mark O'Driscoll, William B. Dobyns, Mitzi Murray, Louis J. Kim, Peter Byers, Michael O. Dorschner, Manuel Ferreira

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. 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 the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic 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 < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. 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.

Original languageEnglish
Pages (from-to)968-976
Number of pages9
JournalAmerican journal of human genetics
Issue number5
StatePublished - May 2 2019


  • aneurysm
  • cerebral aneurysm
  • exome
  • fusiform
  • genetics
  • mosaic
  • mosaicism
  • saccular
  • sequencing


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