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

doi:10.1016/j.ajhg.2019.03.014

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 journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	968-976
Number of pages	9
Journal	American Journal of Human Genetics
Volume	104
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2019.03.014
State	Published - May 2 2019
Externally published	Yes

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2019

Keywords

PDGFRB
aneurysm
cerebral aneurysm
exome
fusiform
genetics
mosaic
mosaicism
saccular
sequencing

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10.1016/j.ajhg.2019.03.014

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Karasozen, Y., Osbun, J. W., Parada, C. A., Busald, T., Tatman, P., Gonzalez-Cuyar, L. F., Hale, C. J., Alcantara, D., O'Driscoll, M., Dobyns, W. B., Murray, M., Kim, L. J., Byers, P., Dorschner, M. O., & Ferreira, M. (2019). Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms. American Journal of Human Genetics, 104(5), 968-976. https://doi.org/10.1016/j.ajhg.2019.03.014

Karasozen, Y, Osbun, JW, Parada, CA, Busald, T, Tatman, P, Gonzalez-Cuyar, LF, Hale, CJ, Alcantara, D, O'Driscoll, M, Dobyns, WB, Murray, M, Kim, LJ, Byers, P, Dorschner, MO & Ferreira, M 2019, 'Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms', American Journal of Human Genetics, vol. 104, no. 5, pp. 968-976. https://doi.org/10.1016/j.ajhg.2019.03.014

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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",

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

note = "Funding Information: 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{\textquoteright}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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2019",

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doi = "10.1016/j.ajhg.2019.03.014",

language = "English (US)",

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T1 - Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

AU - Karasozen, Yigit

AU - Osbun, Joshua W.

AU - Parada, Carolina Angelica

AU - Busald, Tina

AU - Tatman, Philip

AU - Gonzalez-Cuyar, Luis F.

AU - Hale, Christopher J.

AU - Alcantara, Diana

AU - O'Driscoll, Mark

AU - Dobyns, William B.

AU - Murray, Mitzi

AU - Kim, Louis J.

AU - Byers, Peter

AU - Dorschner, Michael O.

AU - Ferreira, Manuel

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2019

PY - 2019/5/2

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N2 - 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.

AB - 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.

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KW - cerebral aneurysm

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KW - mosaicism

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Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

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