Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

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 b 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 autophosphorylation, 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.

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

“…All of the individuals with severe skeletal findings also had (Karasozen et al, 2019;Zhong et al, 2018).…”

“…More restricted mosaic GOF variants of PDGFRB found only in affected tissue have been seen in sporadic myofibromas, and less often in myopericytomas and fusiform aneurysms (Arts et al, 2016;Hung & Fletcher, 2017;Karasozen et al, 2019;Zhong et al, 2018). None of these reports described deep sequencing in affected tissue to detect potential second pathogenic variants, although one described three different pathogenic variants in PDGFRB in three myofibromas in a single individual (Arts et al, 2016).…”

“…At 8 weeks of therapy, his scars had thinned and become less prominent, and his parents report they had to start trimming his fingernails again, which they had not done for some time.4 | DISCUSSIONTo better understand the range of PDGFRB phenotypes, we per-formed detailed genotype-phenotype analysis on a cohort of 74 individuals with known or presumed mutations of PDGFRB, including the 12 individuals reported here and another 62 for whom individuallevel data were provided in prior reports. The cohort included 46 individuals with confirmed PDGFRB pathogenic GOF variants, a PDGFRB+ group (AlQawahmed et al, 2019;Arts et al, 2016;Brasseur et al, 2010;Bredrup et al, 2019;Cheung et al, 2013;Frezin et al, 2015;Gawli nski et al, 2018;Guimier et al, 2019;Johnston et al, 2015;Karasozen et al, 2019;Lepelletier et al, 2017;Minatogawa et al, 2017;Mudry et al, 2017;Murray et al, 2017;Penttinen, Niemi, Vinkka-Puhakka, Johansson, & Aula, 1997;Pond et al, 2018;Takenouchi et al, 2015;Zarate et al, 2019;Zhang et al, 2018;Zufferey et al, 2013), and another 28 with phenotype data only, mostly from older reports-a PDGFRB-S or suspected group(Guimier et al, 2019;Hausbrandt et al, 2010;Holzer-Fruehwald, Blaser, Rossi, Fruehwald-Pallamar, & Thurnher, 2012;Kaplan, Ojemann, Grange, Fuller, & Park, 2002;Kulkarni, Desai, Grundy, & Sergi, 2012;Pelluard-Nehmé et al, 2007;Spadola, Anooshiravani, Sayegh, Jequier, & Hanquinet, 2002). For the purposes of this analysis, we excluded the three individuals with unicentric Castleman disease with PDGFRB variants in affected lymph nodes, as 91% of individuals with unicentric Castleman disease were not found to harbor PDGFRB variants, and several other pathogenic variants were identified in affected tissue of other patients with the same phenotype(Li et al, 2019).4.1 | Phenotype analysis...…”

“…In a recent study of aneurysm specimens, 4/6 isolated fusiform aneurysms were found to have pathogenic GOF variants in PDGFRB, compared to 0/38 saccular aneurysm specimens, although no additional clinical data was provided for these individuals(Karasozen et al, 2019). The index subject had serial vascular imaging, which showed that the aneurysms developed over time in adolescence and adulthood(Karasozen et al, 2019).Vascular abnormalities were common in the cohort. Vascular imaging in subjects LR19-455 and LR19-377a1 were normal in infancy, with no follow-up studies yet obtained.…”

Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era

“…3,8 Of the WES studies in the literature, there was no overlap between the variants in the implicated genes. 67,73,76 It is important to note that numerous studies identify risk loci alone and require further functional validation in order to narrow the number of candidate causative genes at the respective chromosomal locus. However, there are implications for modifier alleles playing a role in intergenic regions that harbor regulatory elements.…”