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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/16129
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dc.contributor.advisorPare, Guillaume-
dc.contributor.authorChong, Michael-
dc.date.accessioned2014-10-22T18:14:20Z-
dc.date.available2014-10-22T18:14:20Z-
dc.date.issued2014-11-
dc.identifier.urihttp://hdl.handle.net/11375/16129-
dc.description.abstractBackground: Rare genetic mutations cause familial early-onset stroke disorders, known as “Mendelian strokes”. The broader relevance of rare mutations in unrelated young stroke patients is uncertain. We hypothesize that rare mutations in known and novel genes are important risk factors for stroke. Methods: Exome sequencing was used to characterize rare disruptive protein-altering mutations in 185 young cases and 185 matched controls from INTERSTROKE, a large and globally representative stroke study. The major objectives were: 1) to precisely define the role of known Mendelian stroke genes and 2) to discover novel gene and pathway associations. Results: A focused assessment of known Mendelian stroke genes revealed a significant contribution from NOTCH3, the causal gene for Cerebral Autosomal Dominant Arteriopathies with Subcortical Infarcts and Leucoencephalopathies (CADASIL). CADASIL mutations were identified in six cases and no controls (P=0.03). The clinical presentation of CADASIL mutation carriers deviated from known symptomatology, consisting of small-vessel ischemic strokes (SVIS) accompanied by secondary features including migraine and depression. A novel role for non-CADASIL NOTCH3 mutations in ICH was also elucidated (OR=2.86; 95% CI, 1.13 to 7.93, P=0.02). Such mutations were present in 22% of ICH cases and 8% of matching controls. An agnostic evaluation of all genes did not reveal any genome-wide significant associations. However, NOTCH3 was among the top ICH genes out of 13,706 tested, and many others were also biologically relevant, notably, AARS2 and NBEAL2. A protective association was identified for the renin angiotensin system (P=8.1x10-4), whereas type II diabetes mellitus was associated with increased risk (P=1.9x10-2). Conclusion: Rare mutations influence risk of early-onset stroke. CADASIL mutations play an important role in unrelated stroke patients. Beyond CADASIL, a novel role was uncovered for other NOTCH3 mutations as common and significant risk factors for ICH. Novel biologically relevant genes and pathways may also affect stroke susceptibility.en_US
dc.language.isoenen_US
dc.subjectExome sequencingen_US
dc.subjectCardiovascular diseaseen_US
dc.subjectStrokeen_US
dc.subjectGeneticsen_US
dc.subjectCerebrovascular diseaseen_US
dc.subjecthemorrhagic strokeen_US
dc.subjectsmall vessel strokeen_US
dc.subjectischemic strokeen_US
dc.subjectCADASILen_US
dc.subjectMendelian strokeen_US
dc.subjectStroke geneticsen_US
dc.subjectRare variantsen_US
dc.subjectINTERSTROKEen_US
dc.subjectNext-generation sequencingen_US
dc.titleEXOME SEQUENCING FOR RARE MUTATIONS IN YOUNG STROKEen_US
dc.title.alternativeEXOME SEQUENCING TO CHARACTERIZE THE ROLES OF MENDELIAN STROKE GENES AND NOVEL GENES IN YOUNG STROKEen_US
dc.typeThesisen_US
dc.contributor.departmentMedical Sciencesen_US
dc.description.degreetypeThesisen_US
dc.description.degreeMaster of Science in Medical Sciences (MSMS)en_US
Appears in Collections:Open Access Dissertations and Theses

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