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UBC Theses and Dissertations

Next generation sequencing to determine a genetic cause of familial intracranial aneurysms Hitchcock, Emma Catherine


Intracranial aneurysms (IA), a common disease that occurs when cerebral arteries weaken and expand, can lead to subarachnoid hemorrhage upon rupture. The prevalence of IA is estimated to be around 3% and is known to increase with age. A small subset of the patient population has a familial form IA, where two or more first- to third- degree relatives have IA. At this time, one gene, THSD1, has been associated with familial IA (FIA). Here we present the preliminary findings from whole exome sequencing on five families diagnosed with FIA. Each family appears to have Mendelian segregation of disease (autosomal dominant, autosomal recessive, or X-linked) and has had their aneurysms clinically confirmed through brain imaging. Sequencing data from the proband of each family was used to identify family-specific candidate genes and was overlapped between families to identify genes that contain rare, possibly pathogenic variants in three or more families. Four genes -- DST, CRIPAK, DNAH1, and TTN --were found to contain rare variants in four out of the five families. Three top candidate genes were selected based on gene function or previous association to cerebral vascular disease from 38 genes that contain rare variants in three out of the five families.

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