31Autism spectrum disorders (ASD) are neurodevelopmental conditions that are influenced by 32 genetic factors and encompass a wide-range and severity of symptoms. The details of how 33 genetic variation contributes to variable symptomatology are unclear, creating a major challenge 34 for translating vast amounts of data into clinically-useful information. To determine if variation 35 in ASD risk genes correlates with symptomatology differences among individuals with ASD, 36 thus informing treatment, we developed an approach to calculate the likelihood of genetic 37 dysfunction in Gene Ontology-defined biological processes that have significant 38 overrepresentation of known risk genes. Using whole-exome sequence data from 2,381 39 individuals with ASD included in the Simons Simplex Collection, we identified likely damaging 40 variants and conducted a clustering analysis to define subgroups based on scores reflecting 41 genetic dysfunction in each process of interest to ASD etiology. Dysfunction in cognition-related 42 genes distinguished a distinct subset of individuals with increased social deficits, lower IQs, and 43 reduced adaptive behaviors when compared to individuals with no evidence of cognition-related 44 gene dysfunction. In particular, a stop-gain variant in the pharmacogene encoding 45 cycloxygenase-2 was associated with having an IQ<70 (i.e. intellectual disability), a key 46 comorbidity in ASD. We expect that screening genes involved in cognition for deleterious 47 variants in ASD cases may be useful for identifying clinically-informative factors that should be 48 prioritized for functional follow-up. This has implications in designing more comprehensive 49 genetic testing panels and may help provide the basis for more informed treatment in ASD. 50 51 65While there are more than one hundred implicated genes, many function in the same 66 biological process(9, 10). Dysfunction in genetic mechanisms encoding different biological 67 functions may contribute independently to increase risk for ASD. For example, one study 68 observed that a subset of individuals with ASD had de novo and rare, inherited variants in 69 synaptic genes but not chromatin modification genes, while another subset had these types of 70 variants in chromatin modification genes but not synaptic genes(11). If some individuals with 71 ASD have dysfunction in a particular biological process while others have dysfunction in a 72 separate process, then it may be possible to use genetic data to inform a more personalized (i.e., 73 precision medicine) approach to treatment of symptoms. However, the study mentioned above, 74 4 and others, have not observed a relationship between genetic and phenotypic differences (11, 12). 75 As such, it is difficult to determine if distinguishing dysfunction across different underlying 76 biological processes is clinically useful. Notably, previous studies have focused largely on 77 evaluating contributions from specific types of genetic variants (e.g., solely de novo and rare 78 varia...