Autism is a highly heritable complex trait, heterogenous in genotype and phenotype. Rare genetic variants, both inherited and de novo, typically have larger effect sizes and are more penetrant than common variants in the population. Next-generation sequencing technologies facilitate simultaneous investigation of variation across the allele frequency spectrum. This thesis aims to investigate rare variation and its contribution to the genetic basis of autism. This study applies genome sequencing to an autism cohort of affected individuals in a family-based study design. (WES n=42, WGS n=35). Variants emerging from these analyses contribute to the existing evidence supporting association of relevant genes with autism. Additionally, this thesis investigates the clinical utility of genome sequencing in autism. Genetic diagnosis in autism is limited by the ability to robustly determine the relevance of putatively pathogenic genetic variation. Through application of an evidence-based gene curation framework and through investigation of the diagnostic yield of commercial gene panels available for use in autism, this thesis informs on current strategies to translate genomics findings into the clinic. Insights into the biological mechanisms underlying autism arising from this research, will lead to a greater understanding of the condition and potentially benefit clinical intervention and treatment plans in the future.