The use of whole exome sequencing to detect novel genetic disorders: Two cases and an assessment of the technology


Over the past several years whole exome sequencing (WES) by high-throughput sequencing of target-enriched genomic DNA has become both technically feasible and financially practical as a means of studying Mendelian disorders. It is also entering the clinical realm as a powerful diagnostic tool for cases that have eluded answers and a cost effective one for cases with a suspected genetically heterogeneous disorder or set of differentials. This thesis examines the strategies for use and impact of such a technology in both the research and clinical setting. It presents an analysis of two cases in which WES was used to determine the causative mutation in the phenotype of an unknown/undiagnosed genetic disorder. The results demonstrate the strengths and limitations of variant filtering strategies, the need for co-segregating familial samples when possible, the value of a detailed phenotypic picture and family history, and value of functional studies in confirming the pathogenicity of candidate variants. In the first case report, WES succeeded in narrowing the candidate list to a manageable size for two sibs affected in the neonatal period with seizures, encephalopathy, and thrombocytopenia, and who died at a few months of age. Sequencing data on the parents and unaffected sibling is needed to elucidate the pathogenic mutations. In the second case report, WES detected a strong candidate mutation in NDUFAF6, a complex 1 assembly factor. Given the patient’s presentation with multi-organ dysfunction, dramatic skeletal myopathy, and degenerative course suggestive of a mitochondrial disorder, complex 1 deficiency was suspected but Sanger sequencing failed to confirm the mutation. This thesis also examined the ethical and practical considerations involved in incorporating WES into clinical practice and its impact on public health, namely improved treatment options for patients and an improved knowledge of the relationship between genetics and disease phenotypes

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