Expanding the utility of whole genome sequencing in the diagnosis of rare genetic disorders

The emergence of whole genome sequencing (WGS) has revolutionized the diagnosis of rare genetic disorders, advancing the capacity to identify the “causal” gene responsible for disease phenotypes. In a single assay, many classes of genomic variants can be detected from small single nucleotide changes to large insertions, deletions and duplications. While WGS has enabled a significant increase in the diagnostic rate compared to previous assays, at least 50% of cases remain unsolved. The lack of a diagnosis is the result of both limitations in variant calling, and in variant interpretation. As the field of genomic medicine continues to advance, the emergence of novel bioinformatic approaches to variant calling and interpretation herald promise for the future of undiagnosed cases. In the applied setting, innovation is driven by anecdotes of complex diagnoses, which in turn lead to the development of novel tools and approaches. This is a key theme within this thesis work, where in-depth analysis of a single undiagnosed case leads to an appreciation for a challenging class of variants–short tandem repeats–which in turn leads to the development of novel software for detecting these variants in WGS data. Following the anecdote and novel tool development came an appreciation for the role of simulation, both in enabling the development and in the uptake of bioinformatic innovation for diagnostic analysis pipelines. This appreciation led to the development of a rare disease scenario simulator, which can simulate complex variants in multiple inheritance patterns to emulate challenging cases. Lastly, appreciating the limitations of the linear reference genome, I develop a framework for detecting the presence of user-specified sequences within unmapped read sets. This flexible framework can reproduce microarray-like coverage profiles, and genotype SNPs to identify ancestry and sex which can inform the choice of personalized reference genomes in emergent analysis pipelines. Together, the novel short tandem repeat discovery, bioinformatic innovation, and increased capacity to simulate rare disease cases, expand the utility of whole genome sequencing in the diagnosis of rare genetic diseases.