UBC Theses and Dissertations

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UBC Theses and Dissertations

An analysis of genetic variants associated with autism spectrum disorder Callaghan, Daniel Benjamin


Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder affecting roughly 1% of the human population. Genomics research to date has discovered only a fraction of the variants causative for ASD. To this end, we whole-genome sequenced a cohort of 119 ASD individuals in order to find likely pathogenic variation. After quality and frequency filters, we prioritized variants as likely causal according to rarity and predicted damage scores (CADD and Snap2). Here, we report five de novo damaging variants and seven likely damaging variants of unknown inheritance. Since much of the variation reported in ASD cases is uncertain both in function and in significance in ASD, we aimed to functionally characterize missense variants from the ASD literature in PTEN and SYNGAP1, two well-characterized ASD genes. We curated missense variants of unknown significance from the ASD literature and assayed their functional effect in yeast using a Synthetic Genetic Array. We chose previously biochemically validated variants, population variants, and other variants in the genes of interest to gain insight into the functional diversity of PTEN and SYNGAP1 variation. We established functional effect of the ASD variants of unknown significance in PTEN and showed that computational predictors of damage are reasonable predictors of variants’ functional effects in yeast. We found that agreement of computational metrics breaks down when predicting damage in certain genes, such as SYNGAP1. Functionalizing variants in this way contributes to our understanding of the range of functional effects of ASD variants. Supplementary materials available at: http://hdl.handle.net/2429/64424

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