Genomic and functional analyses of Newfoundland and Labrador families with intracranial aneurysms

• Main Author: Pennell, Julia
• Format: Thesis
• Language: English
• Published: Memorial University of Newfoundland 2021
• Subjects: Newfoundland
• Online Access: https://research.library.mun.ca/15010/; https://research.library.mun.ca/15010/1/thesis.pdf

The integrity of an arterial wall is impacted by various genetic, environmental, and physiological factors that predispose to intracranial aneurysm (IA) formation in certain individuals. In this study, whole exome sequencing was completed on a large cohort of families from the Newfoundland and Labrador population to identify genetic predispositions contributing to IA development. With the use of Sanger sequencing, HAL (c.959C>T; p.T320M) emerged as a favourable candidate variant, and morpholino mediated gene knockdown of hal in Danio rerio (zebrafish) demonstrated a dose-dependent hemorrhagic phenotype. The re-expression of wildtype HAL RNA in the hal morpholino background was able to rescue the hemorrhagic phenotype while mutant HAL RNA was not. These results suggest that the HAL (c.959C>T; p.T320M) variant could be contributing to IA development in Family R1262. Additional analysis of the HAL gene could help determine the extent of its involvement and contribute to an improved understanding of IA pathogenesis.