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Am J Hum Genet. 2019 May 2;104(5):968-976. doi: 10.1016/j.ajhg.2019.03.014. Epub 2019 Apr 25.

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms.

Author information

1
Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA.
2
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
3
Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RH, UK.
4
Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Center for Integrative Brain Research, Seattle Children's Hospital, Seattle, Washington 98105, USA.
5
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Medicine, Division of Genetics, University of Washington School of Medicine, Seattle, Washington 98195, USA.
6
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Medicine, Division of Genetics, University of Washington School of Medicine, Seattle, Washington 98195, USA.
7
Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.
8
Department of Neurosurgery, University of Washington School of Medicine, Seattle, Washington 98195, USA. Electronic address: manuelf3@uw.edu.

Abstract

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.

KEYWORDS:

PDGFRB; aneurysm; cerebral aneurysm; exome; fusiform; genetics; mosaic; mosaicism; saccular; sequencing

PMID:
31031011
PMCID:
PMC6506794
[Available on 2019-11-02]
DOI:
10.1016/j.ajhg.2019.03.014

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