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. 2019 Apr 25;104(5):968–976. doi: 10.1016/j.ajhg.2019.03.014

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

Yigit Karasozen 1, Joshua W Osbun 1, Carolina Angelica Parada 1, Tina Busald 1, Philip Tatman 1, Luis F Gonzalez-Cuyar 2, Christopher J Hale 2, Diana Alcantara 8, Mark O’Driscoll 8, William B Dobyns 5,6,7, Mitzi Murray 2,4, Louis J Kim 1, Peter Byers 2,3,4, Michael O Dorschner 2,3, Manuel Ferreira Jr 1,∗
PMCID: PMC6506794  PMID: 31031011

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

Main Text

Intracranial aneurysms occur in approximately 2% of the population and have a rupture risk of 6 per 100,000 individual-years.1, 2 There are two types of aneurysms, the more common saccular type (90%–95%) and the fusiform type (4%–8%).1, 2 Saccular aneurysms are abnormal arterial outpouchings at branch points and have histological loss of the media and intima. Fusiform aneurysms are circumferential abnormal arterial dilatation with histological medial and intimal hyperplasia. The size, location in the cerebrovascular tree, and type of aneurysm all influence the natural history of this disease.1, 2 Abundant evidence supports a genetic component to the etiology of intracranial aneurysms.1, 2, 3, 4, 5, 6, 7 The pathogenesis of cerebral-aneurysm formation and rupture is complex and involves both environmental2 and genetic factors defined by twin, linkage, and genome-wide association studies.3, 4, 5 Several genetic syndromes are associated with intracranial aneurysms, and they confer increased risk compared to the risk for the general population.1, 2, 3 Studies in mono- and dizygotic twins also suggest both genetic and environmental contributions.5 Established environmental risk factors, which might somatically alter coding regions of the genome, include cigarette smoking and hypertension.1, 2 The role of post-zygotic variants of genes that function in critical intracellular signaling pathways has been established for several types of overgrowth syndromes8, 9 and vascular malformations,10, 11, 12, 13, 14, 15, 16 but the role of somatic genetic alterations or mosaicism in intracranial aneurysms remains unknown.

The index individual was first treated for a dissecting fusiform paraclinoid internal carotid artery aneurysm at nine years of age. All individuals’ data and specimen collection were reviewed and approved by the University of Washington institutional review board and human subjects division. The individual was noted to have an impressive ipsilateral cutaneous phenotype. 14 years later, he developed a giant dissecting fusiform aneurysm of the right vertebral artery, which was previously normal according to angiography (Figures 1A–C and S1). He had apparently normal cognition and no neurological deficits or other birth defects. No other abnormalities (including intracranial calcifications) were found on brain, cardiovascular, or peripheral vascular imaging. He later developed both radial and coronary artery aneurysms (Figures S1J and S1K), but never an aortic aneurysm or dissection, beneath his dermal phenotype. His family history was negative. The left neurovascular tree remained normal (Figures S1C and S1E). Detailed phenotype information for this individual is shown in Figure S1. He underwent a series of operations for treatment of the giant, rapidly growing fusiform vertebral aneurysm. DNA was extracted from multiple vascular and perivascular tissue samples (Figure 1K) obtained during surgery. Initial variant discovery was carried out via paired-sample exome sequencing to an average depth of ∼150× between blood and fibroblasts derived from the diseased areas (>99% of the exome was covered for all samples). Exome sequencing was performed on blood and abnormal tissue with a customized exome-capture probe set that is built upon the xGen Exome Research Panel v1.0 (IDT) backbone and from the UW Medicine Center for Precision Diagnostics. Initial variant discovery was carried out via a comparison between blood and diseased-area cultured fibroblast exomes sequenced to an average depth of ∼150× on the Illumina HiSeq 2500 platform. Subsequent exome sequencing was performed on other diseased specimens and healthy radial artery (Figures 1K and 1L) to an average depth of at least 40× (>99% of the exome). Resulting reads were aligned with the Burrows-Wheeler Alignment Tool BWA-MEM (v0.7.5) according to the Broad Institute’s Genome Analysis Toolkit (GATK) best practices. Somatic variants were identified via MuTect (v1.1.7) with default parameters. Our analysis detected a single novel variant within the platelet-derived growth factor receptor β gene (PDGFRB) juxtamembrane-coding region (p.Tyr562Cys [g.149505130T>C (GRCh37/hg19); c.1685A>G]). Variant allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue (Figures 1D–1L). No other somatic variants were found. The highest allele fractions were found in a specimen from an occipital artery aneurysm (Figures 1D–1I and S2). This PDGFRB variant was not found in DNA isolated from blood or the histologically normal, left-sided, radial artery (Figures 1J–1L), confirming post-zygotic or somatic mosaicism.

Figure 1.

Figure 1

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Index Individual Phenotype and PDGFRB Genotype

(A) A Body map of skin mosaicism (in red) and the specimens used for exome sequencing.

(B) Cutaneous appearance.

(C) An angiogram 3D reconstruction of a right vertebral injection, illustrating a giant vertebral fusiform aneurysm.

(D–I) Abnormal extra-cranial soft-tissue vasculature associated with the occipital artery (Specimen MOS-WES-3). Low power (4×) (D) and medium power (10×) (E) magnification of a hematoxylin and eosin (H&E)-stained slide demonstrating a markedly affected vessel with focal evidence of dissection (arrowhead). There is severe intimal hyperplasia, and the tunica media (∗) becomes markedly attenuated. Low power (4×) (F) and medium power (10×) (G) magnification of a Gomori trichrome (GT)-stained slide with the intima (∗∗) and the tunica media (∗) highlighted. Low power (4×) (H) and medium power (10×) (I) magnification of a Verhoeff-Van Gieson (VVG)-stained slide. The internal elastic lamina (∗) associated with the relatively better-preserved fragment of tunica media, as well several areas with attenuated internal elastic lamina (∗∗), are highlighted.

(J) An H&E-stained slide of an unremarkable left arm radial artery from specimen MOS-WES-6 at medium power magnification (10×). A well-defined intimal layer, the tunica media, and the tunica adventitia, along with an intact internal elastic lamina (∗), are visualized.(K) Specimens used for exome sequencing and coverage of the p.Tyr562Cys variant.

(L) Next-generation sequencing reads across the area of the missense variant; the variant nucleotides (C) are in blue. The reference nucleotide and amino acid sequences are at the bottom.

PDGFRB encodes a conserved transmembrane receptor tyrosine kinase involved in diverse signaling processes during embryonal development.17, 18, 19, 20, 21 PDGFRB is normally expressed in several cell types, including pericytes and vascular smooth muscle cells, and has an essential role in vascular progenitor cell signaling.19, 20, 21 On the basis of the findings in the individual described above, we performed targeted sequencing of PDGFRB in a validation cohort of 50 aneurysm and arterial walls (Table S1). The validation cohort was sequenced similarly to the exome sequencing performed on the index individual with the exception that a custom capture-probe set (IDT) was used rather than the full exome. Variants were batch-identified across the cohort with the Platypus variant caller (v0.8.1), which used a minimum variant-allele fraction of 2%, a minimum coverage of 5 reads, and a minimum posterior probability of 0 (no variant reads), allowing more inclusive initial analysis. Germline variants and sequencing artifacts were further filtered out with an in-house script. All somatic variants were analyzed with IGV (v2.3.71) and functionally annotated with Oncotator (v1.9.3.0). In three additional sporadic individual cases, targeted sequencing revealed four variants: a juxtamembrane domain variant predicted to result in a four aa in-frame deletion (p.Tyr562_Arg565del) in exon 12, and two additional variants (p.Asp850Tyr and p.Arg849_Lys860delinsHisAlaGlyLeuGluLeuHisLeuGln) in the activation loop of the kinase domain in exon 18 (Figure 2A). The latter variant was comprised of two deletions located in cis, and these deletions together are predicted to result in a complex, in-frame insertion-deletion (Figure S4). Variants were only found in fusiform aneurysms (3/5, 60%), which were radiographically and histologically similar to the aneurysms found in our index individual (Figures 2B–F and S3). All saccular aneurysms had wild-type PDGFRB.

Figure 2.

Figure 2

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Sporadic Fusiform Aneurysms Harbor PDGFRB Variants

(A) Demographics of individuals with sporadic fusiform aneurysms and their variants, including age at treatment.

(B, C, and F) An angiogram and/or 3D reconstruction from angiogram-representative images illustrating the fusiform morphology.

(D and E) Representative H&E-stained sections of specimen VAL-44 at low (1.25×) and medium (10×) magnification showing a markedly affected vessel with vascular wall attenuation, an intraluminal thrombus with early organization, and a dissecting hemorrhage. The tunica media (∗) is focally present and becomes attenuated (∗∗).

(G) H&E-stained sections at low magnification (1.25×) of specimen VAL-61 showing a representative portion of the 3 cm aneurysm with a large, partially organizing thrombus and a markedly attenuated vascular wall. Abbreviations are as follows: AF = allele frequency; ICA = internal carotid artery; MCA = middle cerebral artery; PCA = posterior cerebral artery; and RCCA = right common carotid artery.

Exome sequencing was performed on aneurysm walls and control tissues from all three PDGFRB-variant sporadic fusiform aneurysms (see the Supplemental Data). All aneurysm samples were sequenced to at least a depth of 175× (>99% of exome), and control samples, with the exception of lymph node DNA from the VAL-44 individual, were sequenced to a depth of at least 90× (>99% of exome) average coverage. Additional sequencing was added to the PDGFRB variant region of the lymph node DNA (non-aneurysm control DNA) with the custom capture-probe set in order to study a germline contribution for VAL-44. The aneurysm exome of VAL-44 was analyzed on its own. For every available control tissue, complete pairs were analyzed with a variant via FreeBayes (v1.0.2), Strelka2 (v2.0.17), VarDict (v1.5.1), and VarScan2 (v2.4.3), and the output was filtered with an in-house script and confirmed with manual inspection on IGV. For the VAL-44 aneurysm without a good-quality control, variant calling was done with FreeBayes, Platypus, and VarDict, and the output was filtered with an in-house script and confirmed with manual inspection on IGV. Exome sequencing of aneurysm and normal tissue DNA revealed only recurrent PDGFRB variants (Figure S4 and Table S3), suggesting a causal role in the formation of sporadic fusiform aneurysms. DNA was available from blood and/or unaffected healthy tissue, allowing for the exploration of the germline contribution of the variant in all cases (Table S3).

The skewed PDGFRB allele fractions, in sporadic fusiform aneurysms, ranged from 5.6 to 21.4% (Figure 2A), also consistent with post-zygotic, somatic variants. These results were also confirmed by next-generation sequencing after independent primer-pair amplification across the variant locations, resulting in similar allele fractions (Tables S2 and S3). Two of the PDGFRB missense variants observed (p.Tyr562Cys and p.Asp850Val) have recently been found in sporadic myofibromas.22, 23 None of the variants we detected in intracranial aneurysms was seen in >120,000 normal genomes (from dbSNP, 1000 Genomes, NHLBI-EVS, and the gnomAD databases); this finding supports their pathogenicity and suggests that they might be embryonic lethal. These variants altered conserved regions and were predicted to be protein-altering and pathogenic by PolyPhen2, SIFT, and MutationTaster (Figure S5).

In fusiform aneurysms, missense variants and in-frame deletions occurred in either the ArgTyrGluIleArg motif of the juxtamembrane region or the adjacent AspPheGly motif in the activation loop (Figures 3A–C and S5) of PDGFRB. Disruption of juxtamembrane region auto-inhibitory sites causes constitutive activation.24, 27 All four variants occur in known homologous PDGFRA and KIT “hot spots” within the juxtamembrane or the activation loop of the kinase domains.24, 25 The conserved residues are found in all tyrosine protein kinases, and the analogous residues (Tyr555 and Tyr552) in the PDGFRA and KIT kinases are somatically altered in cancers24, 25 (Figure 3B). The aneurysm alterations in PDGFRB are predicted to result in p.Tyr562Cys and p.Tyr562_Arg565del. Aligned amino-acid sequences of the activation loops of human KIT, PDGFRA, and PDGFRB start and end with residues AspPheGly and AlaProGlu. Within the kinase loop, the two alterations that are known to be important for autoregulation24, 25, 28, 29 were p.Asp850Tyr and an in-frame deletion and insertion spanning this region (Figure 3C). These data suggest that variants found in cerebral aneurysms act via gain-of-function mechanisms. Deep, targeted sequencing of the genes coding for the kinases KRAS, PDGFRA, BRAF, TGFBR1, and TGFBR2 identified no variants in the cohort of 50 aneurysms, consistent with an etiology specific to PDGFRB.

Figure 3.

Figure 3

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Variants in PDGFRB Within the Juxtamembrane Region and the Kinase Activation Loop Found in Fusiform Aneurysms

(A) A schematic representation of the PDGFRB protein, the amino acid sequence of the two hotspots, and the location of variants. Germline and somatic PDGFRB variants with known or implied functional consequences in other syndromes and diseases are included for comparison.

(B) Homologous juxtamembrane amino acid sequences for KIT, PDGFRA, and PDGFRB and the location of aneurysm variants.

(C) Homologous kinase-domain activation-loop amino acid sequences for KIT, PDGFRA, and PDGFRB and the location of aneurysm mutations.

(D) All somatic variants with possible activating consequences (missense and in-frame insertions and deletions) reported in the COSMIC database for KIT, PDGFRA, and PDGFRB. Notice the increased frequency of variants in both the juxtamembrane region and the kinase activation loop of KIT and PDGFRA. There is a comparative lack of variants reported in PDGFRB.

Several heterozygous germline or mosaic gain-of-function variants in PDGFRB result in infantile myofibromatosis (IM; MIM: 228550) or sporadic myofibromas, and single, heterozygous germline variants were found in the rare Kosaki overgrowth (MIM: 616592) and Penttinen syndromes (MIM: 601812) (Figures 3 and Table S2). Several other heterozygous, germline loss-of-function variants cause primary familial brain calcification (PFBC; MIM: 615007). None of the above phenotypes were found in our four aneurysm-affected individuals (Table S2). Genome copy-number alterations, including chromosome 5 deletions encompassing PDGFRB, have been associated with developmental delay but not with aneurysm development in affected individuals.26 Mice deficient in Pdgfb or Pdgfrb die from multiple developmental defects including hemorrhages due to a lack of pericytes and vascular smooth muscle cells in blood vessels.17, 18, 19, 20 Mutation that activate Pdgfrb in mice cause vascular smooth muscle cell de-differentiation, hyperplasia, and increased extracellular-matrix synthesis.20 The wide range of phenotypes suggests a complexity of PDGFRB function and downstream signaling that is likely a result of cell lineage and developmental-timing-specific expression.

To study the functional status of PDGFRB variants, we performed assays by using cells collected from skin punches of the index individual (healthy and affected regions), and we performed site-directed mutagenesis by using the QuickChange II Site-Directed Mutagenesis Kit (Catalog #200518, Agilent Technologies). For details, see the Supplemental Data. Ligand binding induces PDGFRB dimerization and activates autophosphorylation in trans. Phosphorylation on multiple tyrosine residues creates docking sites for signaling proteins, including phosphatidylinositol-3 kinase (PI3K), AKT, STAT transcription factors, and phospholipase Cγ (PLCγ).27, 28, 29, 30, 31 Starved mosaic fibroblasts harvested from the index individual and predicted to express the Tyr562Cys variant had higher basal levels of pPDGFRB, pSRC (Tyr416), pAKT (Ser473), and pERK 1/2 (Thr202/Tyr204) (Figures 4A and 4B). PDGF-BB was able to further autophosphorylate PDGFRB and activate downstream signaling (Figure 4B). To investigate the pathogenic mechanism of all discovered variants, we ectopically expressed the wild type (WT), aneurysm-associated variants, and two controls in human embryonic kidney (HEK) cells (Figure 4C). All four aneurysm-associated variants caused higher levels of autophosphorylation of PDGFRB when compared to WT. We next tested the ability of the multi-targeted receptor tyrosine kinase inhibitor sunitinib (Sutent) to downregulate auto-phosphorylation of PDGFRB variants (Figure 4D). Although all of the intracranial aneurysm variants exhibited relative resistance to sunitinib compared to WT PDGFRB under these conditions, three could be strongly inhibited. In contrast, the p.Asp850Tyr variant exhibited marked resistance to sunitinib under these conditions. Interestingly, kinase-inhibitor resistance was also reported for p.Asp850Val, similar to the p.Asp842Tyr PDGFRA and p.Asp816Val KIT variants in gastrointestinal stromal tumors.24, 25

Figure 4.

Figure 4

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PDGFRB Variants are Constitutively Phosphorylated, Sensitive to Sunitinib Kinase Inhibition, and Activate Downstream Signaling Pathways

(A) An immunoblot analysis of non-starved normal (wild-type PDGFRB) and mosaic-affected Tyr562Cys fibroblast cells from the index individual.

(B) An immunoblot analysis of starved and PDGF-BB-stimulated normal (wild-type PDGFRB) and mosaic-affected Tyr562Cys fibroblast cells from the index individual.

(C) An immunoblot analysis of HEK cells stably expressing the described aneurysm variants and Trp566Arg (IM; gain of function) and Asp844Gly (PFBC; loss of function) control variants showing varying levels of phosphorylation and expression of PDGFRB.

(D) Sensitivity of PDGFRB auto-phosphorylation to sunitinib.

Band intensity was quantified compared to beta-actin, and relative band densitometry is presented as the mean ± SEM of three separate blots in triplicate.

Exome sequencing of the index individual allowed us to study of the role of somatic alterations in aneurysm formation. A single post-zygotic, somatic PDGFRB variant, predicted to cause a gain-of-function protein, was discovered. This observation in the index individual provided the proof in principle that alterations in PDGFRB might be found in sporadic, non-mosaic individuals. Here we describe variants of PDGFRB as a cause of single and multiple fusiform aneurysms. The role of somatic mosaicism has been described in overgrowth syndromes (e.g., AKT18 and PIK3CA9), Sturge-Weber syndrome (GNAQ11), and head and neck12, 13, 14, 15 and cerebral arterial-venous malformations (KRAS16). Following this theme, PDGFRB activating variants of the cerebral vasculature seem to drive aneurysm formation. We describe the first reported genetic cause of any type of sporadic intracranial aneurysm: activating variants in PDGFRB. We used exome sequencing and targeted deep sequencing to explore the genetic landscape of cerebral aneurysms. A somatic point variant that was predicted to result in a tyrosine to cysteine (p.Tyr562Cys) change and was within the conserved, auto-inhibitory, juxtamembrane region of PDGFRB was identified. To explore the possibility of additional driving mutations and genetic similarities, we performed exome sequencing in all fusiform aneurysms. This confirmed the following: (1) exome sequencing of PDGFRB-variant fusiform aneurysms revealed no additional detectable, recurrent gene alterations consistent with a causal relationship; (2) two of the fusiform aneurysms carried wild-type PDGFRB and had no evidence of a novel driver variant; and (3) exome sequencing of multiple abnormal tissue specimens from PDGFRB-variant patients revealed a definitive role for somatic mosaicism in two of four individuals.

Activating PDGFRB variants underlie sporadic fusiform aneurysms, suggesting an important role in cerebral artery angiogenesis. Four of six fusiform aneurysms carried PDGFRB activating variants, highlighting the importance of this pathway. Two fusiform aneurysms were found to harbor no PDGFRB alterations, even after deep sequencing, suggesting that there is another gene or mechanism in formation or that ultra-low variant-allele fractions were not detected. Although our exome sequencing was sensitive enough (150× coverage) to detect PDGFRB variants, it is possible that we were unable to detect ultra-low-level variants in other novel contributing genes. The re-sequencing of PDGFRB with, on average, 400× coverage, in both wild-type fusiform and saccular aneurysms should detect allele frequencies down to 1%. Although we examined pathologic tissue specimens, we concede our techniques would not allow detection of low-frequency, fractional (<1%) variants with certainty.

The activation of protein kinases by a somatic variant or chromosomal alteration is a common mechanism of overgrowth syndromes,8, 9 vascular malformations,10, 11, 12, 13, 14, 15, 16 and tumorigenesis.24, 25 Although variants in PDGFRA and PDGFB might be oncogenic, very few variants of PDGFRB have been described in cancer24 (Figure 3D). Chromosome translocations that cause gene fusions have been reported in rare cases of imatinib-sensitive myeloid neoplasms with eosinophilia.34 Collectively, our functional studies demonstrate elevated auto-phosphorylation of variant PDGFRB and consequent activation of AKT, SRC, and ERK. PDGFRB is essential in the propagation of cerebral pericytes and is a surface marker for these cells, which are thought to give rise to the vascular smooth muscle layer of the arterial media.18, 19, 20, 21, 27, 28, 29, 30, 31 Because PDGFRB is highly expressed in and plays an essential role in pericyte development,18, 19, 20, 21, 27, 28, 29, 30, 31 our data suggest that fusiform aneurysms might originate from cerebral pericytes, vascular smooth muscle cells, or their progenitors.

Alterations result in activated PDGFRB alleles with differential sensitivity to kinase inhibitors, suggesting a potential role for therapeutic intervention. Direct inhibition of activated receptor tyrosine kinases might be a promising approach to aneurysm therapy, and further research is warranted. Where resistance is encountered, for example in the p.Asp850Tyr variant described in this study, kinase inhibitors to downstream targets (e.g., AKT and ERK) represent an alternative strategy. The PDGFRB variants detected in both fusiform intracranial aneurysms and myofibromas cluster in the same two regions (the juxtamembrane and the activation loop of the kinase domain), and they have one variant in common (p.Tyr562Cys) and another involving the same codon (p.Asp850Tyr in intracranial aneurysms and p.Asp850Val in myofibromas). It is striking that none of the variants are reported to occur in the germline but are tolerated in a mosaic pattern. It is unknown if PDGFRB variants cause both cerebral aneurysms and myofibromas in the same individual, but there might be overlap. Although the individuals described in this manuscript had no evidence of myofibromas, renal and iliac aneurysms have been reported in an individual with IM.35 More research is necessary to understand the role of age- or timing-specific intracranial-aneurysm formation. PDGFRB-targeted therapy for treatment of severe IM in an individual with a heterozygous germline mutation in PDGFRB has been reported.36

Fusiform aneurysms of the neurovascular tree are difficult to treat and can rupture and cause vessel occlusion or mass effect on nearby perforator vessels, resulting in neurologic deficits.1, 2, 32, 33 The securing of the aneurysm prior to rupture through maintenance of cerebral blood flow is the goal. Fusiform cerebral aneurysms are difficult to treat with surgery or with endovascular techniques such as stent or coil reconstruction.32, 33 Regardless of treatment option, outcomes for fusiform aneurysm are poor,32, 33 highlighting a need for improved therapies for this select group of vascular lesions. The data presented suggest that some fusiform cerebral aneurysms are caused by activating variants in PDGFRB. The identification of PDGFRB variants in a subset of human fusiform aneurysms and the association between variant and kinase-inhibitor efficacy extend the role of overactive kinase activity in vascular pathogenesis. The striking differences in PDGFRB variants found in fusiform versus saccular aneurysms raise the possibility of unique genetic landscapes and molecular pathogenesis underlying this heterogeneity. Our cohort is limited, and adequate study will require a much larger cohort from multiple centers. These findings provide a model for understanding post-zygotic genetic alterations that cause sporadic aneurysms, which might occur over the lifetime of individuals. The role of somatic PDGFRB variants in fusiform aneurysms has shed light on a pathogenic mechanism in intracranial aneurysms. This finding might aid in the identification of additional causative somatic intracranial aneurysm genes. The identification of recurrent PDGFRB alterations provides an avenue of study for tyrosine-kinase inhibition as a future therapeutic strategy in fusiform cerebral aneurysms.

Declaration of Interests

The authors declare no competing interests.

Acknowledgements

The authors thank the individuals and families for their participation and Drs. Michael Levitt, Raj Ghodke, Laligam Sekhar, and Virginia Sybert for their roles in discussions pertaining to the index individual. Research reported in this publication was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award number P30CA015704 (G. Gilliland, PI), which supports the Northwest (NW) BioTrust and NW BioSpecimen core services; the National Institute of Neurological Disorders and Stroke (NINDS) of the NIH under award number R01HL130996 (W.B. Dobyns, PI); the National Center for Advancing Translational Sciences (NCATS) of the NIH under award number UL1 TR000423 (M. Disis, PI), which supports the Institute of Translational Health Sciences; Cancer Research UK (to M.O’D.); the University of Washington School of Medicine and Department of Pathology; the Fred Hutchinson Cancer Research Center; and the University of Washington Department of Neurosurgery, Goertzen Foundation, and Kapogiannatos Family fund (to M.F.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or the decision to submit the manuscript for publication.

Published: April 25, 2019

Footnotes

Supplemental Data can be found online at https://doi.org/10.1016/j.ajhg.2019.03.014.

Web Resources

Supplemental Data

Document S1. Supplemental Material and Methods, Supplemental References, Figures S1–S5, and Tables S1–S5
mmc1.pdf (1.3MB, pdf)
Document S2. Article plus Supplemental Data
mmc2.pdf (3.8MB, pdf)

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Associated Data

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Supplementary Materials

Document S1. Supplemental Material and Methods, Supplemental References, Figures S1–S5, and Tables S1–S5
mmc1.pdf (1.3MB, pdf)
Document S2. Article plus Supplemental Data
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