Genetic syndromes associated with autism spectrum disorder (ASD) have been studied intensely in the hope of understanding the biology of these disorders and of ASD in general. These ASDs associated with mutations have become an important part of a genotype-first strategy for parsing the heterogeneity of ASD, illuminating the pathophysiology, and defining targets for pharmacological treatment. Prime examples include research on Fragile X and copy number variants such as 16p11.2 and 22q11.2. However, it remains unknown how well treatments based on these genetically defined forms of ASD will generalize to ‘idiopathic’ ASD. This uncertainty stems from the genomic heterogeneity of ASD and from the phenotypic heterogeneity within each syndrome. This panel examines four examples of this genotype-first strategy: Fragile X, 22q11.2 copy number variants, and disruptions in SCN2A and DYRK1A. Discussion will focus on phenotypic heterogeneity, implications for translational research, and the challenges to assessing clinical outcomes. Presentations will include an analysis of familial phenotypes (DYRK1A), identification of a critical region for ASD risk in 22q11.2, genotype-phenotype correlations observed in SCN2A mutations, and differences in language and social communication trajectories between idiopathic ASD and Fragile X syndrome.