Anna Michelle Lehman
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INTRODUCTION: Familial intracranial aneurysms (FIA) may present with Mendelian inheritance and an increased risk for first-degree relatives to develop intracranial aneurysms, at a younger age, and with a higher risk of them rupturing in comparison to their sporadic counterparts. However, since genetic research on this non-syndromic condition began in the early 2000’s only a few disease-gene associations have been discovered and much of the aetiology is still missing. Most of these genetic studies have focused primarily on European and East Asian populations although IA has been well documented in Canadian and Greenlandic Inuit. To our knowledge, we are presenting the first extensive whole genome sequencing study on FIA in several First Nation families from a community in Northwestern British Columbia, Canada.METHODS: Whole genome sequencing was completed for 6 affected individuals, selected for having as distant a relationship as possible. To identify single nucleotide variations, small indels, mitochondrial variations, and structural variations that could cause FIA, various filtration strategies which included read depth and genotype quality controls, gnomAD minor allele frequencies, sequence ontology, and allele sharing between five or more participants were used. Filtered variants were subsequently prioritized based on extensive annotation information and biological significance thorough a literature search.RESULTS: We found 25 single nucleotide variations that passed the initial filtration strategy. After prioritization, seven top variant candidates in the HEMK1, CPT1A, LOC105371356, TUSC3, PLCB3, DKK3, and KRT8 genes remained. Extensive annotation and literature search results demonstrated that the PLCB3 p.R874Q missense variant was the strongest among the seven top variant candidates. However, without a population specific variantivdatabase to permit identification and removal of common population-specific variants no further prioritization could be completed.CONCLUSION: From available data, rare variants were found in this family, but without adequate Indigenous representation in variant databases, interpretation accuracy is limited. Future studies of this family should utilize linkage to localize a single region if possible and also long-read sequencing potentially in order to ensure all variants in a linked region have been identified. The present study has largely ruled out currently known Mendelian disorders associated with intracranial aneurysms.