Somatic Mosaicism of a PDGFRB Activating Variant in Aneurysms of the Intracranial, Coronary, Aortic, and Radial Artery Vascular Beds

• Published in: Journal of the American Heart Association Vol. 11; no. 4; p. e024289
• Main Authors: Parada, Carolina A, El-Ghazali, Fatima M, Toglia, Daphne, Ruzevick, Jacob, McAvoy, Malia, Emerson, Samuel, Karasozen, Yigit, Busald, Tina, Nazem, Ahmad A, Suranowitz, Shaun M, Shalhub, Sherene, Marshall, Desiree A, Gonzalez-Cuyar, Luis F, Dorschner, Michael O, Ferreira, Jr, Manuel
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 15-02-2022; Wiley
• Subjects: Basilar Artery; cerebral aneurysm; fusiform; Humans; Intracranial Aneurysm - genetics; Intracranial Aneurysm - pathology; mosaic; Mosaicism; Original Research; PDGFRB; Radial Artery - pathology; Receptor, Platelet-Derived Growth Factor beta - genetics; PDGFRB; mosaic; fusiform; cerebral aneurysm
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.121.024289

Background Activating variants in platelet-derived growth factor receptor beta (PDGFRB), including a variant we have previously described (p.Tyr562Cys [g.149505130T>C [GRCh37/hg19]; c.1685A>G]), are associated with development of multiorgan pathology, including aneurysm formation. To investigate the association between the allele fraction genotype and histopathologic phenotype, we performed an expanded evaluation of post-mortem normal and aneurysmal tissue specimens from the previously published index patient. Methods and Results Following death due to diffuse subarachnoid hemorrhage in a patient with mosaic expression of the above PDGFRB variant, specimens from the intracranial, coronary, radial and aortic arteries were harvested. DNA was extracted and alternate allele fractions (AAF) of
were determined using digital droplet PCR. Radiographic and histopathologic findings, together with genotype expression of
were then correlated in aneurysmal tissue and compared to non-aneurysmal tissue. The
variant was identified in the vertebral artery, basilar artery, and P1 segment aneurysms (AAF: 28.7%, 16.4%, and 17.8%, respectively). It was also identified in the coronary and radial artery aneurysms (AAF: 22.3% and 20.6%, respectively). In phenotypically normal intracranial and coronary artery tissues, the
variant was not present. The
variant was absent from lymphocyte DNA and normal tissue, confirming it to be a non-germline somatic variant. Primary cell cultures from a radial artery aneurysm localized the
variant to CD31-, non-endothelial cells. Conclusions Constitutive expression of PDGFRB within the arterial wall is associated with the development of human fusiform aneurysms. The role of targeted therapy with tyrosine kinase inhibitors in fusiform aneurysms with
mutations should be further studied.