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Somatic PDGFRB activating variants in fusiform cerebral aneurysms

journal contribution
posted on 2023-06-09, 17:41 authored by Yigit Karasozen, Joshua W Osbun, Carolina Angelica Parada, Tina Busald, Philip Tatman, Luis F Gonzalez-Cuyar, Christopher J Hale, Diana AlcantaraDiana Alcantara, Mark O'DriscollMark O'Driscoll, William B Dobyns, Mitzi Murray, Louis J Kim, Peter Byers, Michael O Dorschner, Manuel Ferreira
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 ß 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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

American Journal of Human Genetics

ISSN

1537-6605

Publisher

Elsevier

Issue

5

Volume

104

Page range

968-976

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-04-30

First Open Access (FOA) Date

2019-10-25

First Compliant Deposit (FCD) Date

2019-04-30

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