| Summary: | The study of how genotypes encode phenotypes is germane if not central to every area of genetics research. This thesis focuses on the application of targeted and Whole Exome Sequencing (WES) in the discovery, identification and understanding of Mendelian disorders primarily with Spinocerebellar Ataxia(s) (SCA) phenotypes. Analogous to Mendelian disorders as a whole, SCA are a complex group of disorders with both shared and unique clinical symptoms. Currently, 28 genetically unique forms of autosomal dominant SCA have been identified. This thesis begins by exploring the potential role of targeted Next Generation Sequencing (NGS) as a clinical and diagnostic tool. The benefits of using targeted sequencing in a clinical setting are two-fold. First, it presents the opportunity to rapidly screen symptomatic individuals for all known genetic variants associated with ataxia phenotypes, thereby greatly increasing the likelihood and accuracy of a diagnosis. Second, symptomatic patients who test negative for all known variants may harbor a novel genetic variant. The identification of novel forms of SCA is of great importance both clinically and in basic research. As a case in point, this thesis uses WES to identify the genetic basis of a rare autosomal dominant SCA affecting a multi-generational kindred of Canadian European descent. Four affected and two unaffected individuals spanning three generations have been sequenced to identify the causal variant. The ability of WES to identify the pathogenic variant of a Mendelian disorder from only four affected individuals is a significant benchmark in genomics research. It is both feasible and probable that as reference databases become more extensive, the genetic diagnosis of human disease from a single affected individual will be common practice. This thesis concludes by examining Mendelian disease variants from a broader perspective. Large exome variant cohorts of asymptomatic individuals are examined for the presence of known pathogenic Mendelian variants. The presence of such variants in a reference database is empirical evidence that pathogenic variants, while necessary, are not sufficient to cause many Mendelian disorders. Specifically, we demonstrate that variable penetrance and expressivity are pervasive factors in Mendelian genetics that have yet to be fully appreciated.
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