Browsing by Author "Maroilley, Tatiana"
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Item Open Access Rare disorders have many faces: in silico characterization of rare disorder spectrum(2022-02-22) Frederiksen, Simona D.; Avramović, Vladimir; Maroilley, Tatiana; Lehman, Anna; Arbour, Laura; Tarailo-Graovac, MajaAbstract Background The diagnostic journey for many rare disease patients remains challenging despite use of latest genetic technological advancements. We hypothesize that some patients remain undiagnosed due to more complex diagnostic scenarios that are currently not considered in genome analysis pipelines. To better understand this, we characterized the rare disorder (RD) spectrum using various bioinformatics resources (e.g., Orphanet/Orphadata, Human Phenotype Ontology, Reactome pathways) combined with custom-made R scripts. Results Our in silico characterization led to identification of 145 borderline-common, 412 rare and 2967 ultra-rare disorders. Based on these findings and point prevalence, we would expect that approximately 6.53%, 0.34%, and 0.30% of individuals in a randomly selected population have a borderline-common, rare, and ultra-rare disorder, respectively (equaling to 1 RD patient in 14 people). Importantly, our analyses revealed that (1) a higher proportion of borderline-common disorders were caused by multiple gene defects and/or other factors compared with the rare and ultra-rare disorders, (2) the phenotypic expressivity was more variable for the borderline-common disorders than for the rarer disorders, and (3) unique clinical characteristics were observed across the disorder categories forming the spectrum. Conclusions Recognizing that RD patients who remain unsolved even after genome sequencing might belong to the more common end of the RD spectrum support the usage of computational pipelines that account for more complex genetic and phenotypic scenarios.Item Open Access Whole genome sequencing facilitates intragenic variant interpretation following modifier screening in C. elegans(2021-11-13) Jean, Francesca; Stasiuk, Susan; Maroilley, Tatiana; Diao, Catherine; Galbraith, Andrew; Tarailo-Graovac, MajaAbstract Background Intragenic modifiers (in-phase, second-site variants) are known to have dramatic effects on clinical outcomes, affecting disease attributes such as severity or age of onset. However, despite their clinical importance, the focus of many genetic screens in model systems is on the discovery of extragenic variants, with many labs still relying upon more traditional methods to identify modifiers. However, traditional methods such as PCR and Sanger sequencing can be time-intensive and do not permit a thorough understanding of the intragenic modifier effects in the context of non-isogenic genomic backgrounds. Results Here, we apply high throughput approaches to identify and understand intragenic modifiers using Caenorhabditis elegans. Specifically, we applied whole genome sequencing (WGS) to a mutagen-induced forward genetic screen to identify intragenic suppressors of a temperature-sensitive zyg-1(it25) allele in C. elegans. ZYG-1 is a polo kinase that is important for centriole function and cell divisions, and mutations that truncate its human orthologue, PLK4, have been associated with microcephaly. Combining WGS and CRISPR/Cas9, we rapidly identify intragenic modifiers, show that these variants are distributed non-randomly throughout zyg-1 and that genomic context plays an important role on phenotypic outcomes. Conclusions Ultimately, our work shows that WGS facilitates high-throughput identification of intragenic modifiers in clinically relevant genes by reducing hands-on research time and overall costs and by allowing thorough understanding of the intragenic phenotypic effects in the context of different genetic backgrounds.