Laura Arbour

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.

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The p.P479L (c.1436C>T) variant of hepatic CPT1A is frequent in Inuit and British Columbia First Nations populations of Canada. CPT1A is a major regulatory point in long chain fatty acid oxidation in the liver. CPT1A deficiency is an autosomal recessive disorder that causes metabolic decompensation triggered by fasting, which can progress to seizures and sudden death, if not treated. This study assesses prevalence and clinical impact of the P479L variant in the Canadian territories and reviews modifiable risk factors associated with infant mortality (IM) in Nunavut.Methods: Ethics approval was obtained from university REBs and local research institutes, with consultation with territorial Aboriginal groups. Newborn screening blood spots from all infants born in 2006 (n=1584) and sudden death in infancy cases (n=31; 1999-2008) in the territories were genotyped for the P479L variant. Results: P479L homozygosity in each territory was 64%, 3%, and 1% for Nunavut, NWT, and Yukon, respectively. Within NWT, homozygosity was highest in Inuvialuit (21%) and very low in First Nations (1%). Homozygosity in sudden death cases was highest in Nunavut (18/20) and associated with an increased risk (OR: 5.15; 95% CI: 1.19-22.38). Homozygosity was 29% for NWT cases (2/7), 67% in NWT Inuvialuit (2/3), and was not present in Yukon cases (0/4). Review of Nunavut IM cases (n=78; 1999-2008) identified Sudden Infant Death Syndrome (SIDS) and Sudden Unexpected Death in Infancy (SUDI) as the leading causes of infant death (47%), followed by death due to infectious disease (28%). At least 23% of IM cases were premature. Discussion: The P479L variant is very frequent in the Inuit/Inuvialuit of Canada. Although the sample size was small, there was an associated risk for sudden death in infants homozygous for the variant in Nunavut. SIDS and SUDI are the leading causes of infant death in Nunavut, followed by death due to infectious disease. Since deaths in these two categories are largely preventable, prevention strategies and further exploration into the P479L variant and other determinants are indicated. Management strategies, including newborn screening for the P479L variant, need to be developed in consultation with health authorities, local medical professionals, and local communities.

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There is a disproportionately high rate of hereditary Long QT Syndrome (LQTS) in Northern British Columbia First Nations people, partly due to a novel missense mutation in KCNQ1 (V205M). The effect has been previously described (Arbour et al, 2008) predisposing those affected to syncope, arrhythmia and sudden death. A community based participatory research approach has enabled over 250 community members to take part, identifying more than 40 carriers of the mutation. Although a great deal of previous research has been carried out on the biological aspects of LQTS, there has been little study into the impact of living with a mutation that predisposes one to sudden death, and no previous studies have provided cultural insights into the issues a remote First Nations community might face. The goal of this thesis was to explore what facilitates and hinders resiliency and coping for those living with LQTS. Participants were invited to partake in their choice of one to one interviews, Photovoice, and Talking Circles. Interviews were recorded, transcribed, and analyzed qualitatively using the Systematic Text Condensation method. Twelve women shared their personal experiences of living with LQTS; eight participated in individual interviews, two participated in the Talking Circle, and two participated in both. Six of the women had known mutations, one was mutation negative, and five were awaiting genetic results. Most had affected children. In general, learning about a LQTS diagnosis was perceived as traumatic, with gradual acceptance that lead to coping. The main factors that facilitate resiliency and coping were positive family relationships, spiritual faith, and knowledge about LQTS. The main factors that hinder resiliency and copying were a poor understanding of the biological or clinical aspects LQTS, conflicting medical advice, especially about necessary physical restrictions, and LQTS not being taken seriously by both social contacts and health care providers. It appeared that learning to live with LQTS is an ongoing process, requiring balance and interconnectedness between all aspects of wellbeing. These issues warrant further exploration. Recommendations to enhance genetic counselling within FN communities will be presented to reflect the Medicine Wheel concept.

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