Investigation of Rare Genetic Variation in Autism Spectrum Disorder by Genomic Screens

Autism spectrum disorder (ASD) is a collection of neurodevelopmental disorders characterized by deficits in social communication and restricted, repetitive patterns of behavior or interests. ASD is highly heritable, however known genetic factors that contribute to ASD explain ~30% of cases, with each factor contributing to <1% of cases. The genetic and phenotypic heterogeneity of ASD reduces the power to identify causative genes. Furthermore, even with the growing number of known ASD genes, our knowledge into the biological pathways underpinning ASD is limited. During my dissertation work I performed three genomic screens with distinct methodologies, aiming to effectively identify rare variants in ASD genes that can help pinpoint functional pathways underlying the disorder. Two of the screens were in patient cohorts, where my methodology was geared to utilize the recent (Chapter 2) or distant (Chapter 3) shared ancestry between parents to identify rare inherited variants and risk loci in affected individuals. I was able to identify coding and noncoding potentially causative ASD variants in known and candidate ASD genes (Chapters 2 and 3), and ancestry-specific genomic loci that conferred ASD risk (Chapter 3). To counteract the sample size limitations of human studies, I performed a forward genetics screen in mice to identify mutations associated with ASD-like behaviors (Chapter 4). I identified mutations linked to altered vocalization and altered repetitive and social behavior phenotypes in mice. To show the synergy of the different methodologies, I performed functional clustering and gene ontology analyses on the combined set of known and candidate ASD genes I identified in all three screens and showed that they converge on cellular pathways that have been previously associated with ASD (Chapter 5). Together, these findings contribute to our knowledge of the genetic underpinnings of ASD and related neurodevelopmental disorders.