Date of Award

2020

Document Type

Thesis

Degree Name

Bachelors

Department

Natural Sciences

First Advisor

Leininger, Elizabeth

Area of Concentration

Neurobiology

Abstract

The role that somatic genetic variants have towards the development of intracranial-aneurysm formation is unknown. The Ferreira lab, at the University of Washington Medical Center, identified a 23-year old man with progressive, right-sided intracranial aneurysms that were lateralized and who had pigmentation of his skin localized to his right side. He underwent a succession of genetic evaluations for known connective-tissue disorders, but these were unrevealing. Initial paired-sample exome sequencing between blood and fibroblasts derived from the patient’s affected areas detected a gain-of-function mutation predicted to cause a p.Tyr562Cys change within the platelet-derived growth factor receptor b gene (PDGFRB). Initial variant-allele fractions ranged from 18.75% to 53.33% within histologically aberrant tissue, indicating somatic mosaicism. The lab also further assessed a group of aneurysm specimens from varying patients and additionally found PDGFRB variants in 4/6 fusiform aneurysms. To further uncover regions of the patient’s body that contained varying allele frequencies, I conducted digital droplet polymerase chain reaction on several tissue specimens which revealed: 0.1% to 53.33% of alternate allele frequencies (AAF) for PDGFRB in these tissues. However, further samples will be required to be run through this experimental assay, to further uncover where else the patient had varying AAF values. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform intracranial aneurysms and suggest a potential role for target therapy kinase inhibitors for future therapies.

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