Calculating the Effects of Autism Risk Gene Variants on Dysfunction of Biological Processes Identifies Clinically-Useful Information

Abstract Autism spectrum disorders (ASD) are neurodevelopmental conditions that are influenced by genetic factors and encompass a wide-range and severity of symptoms. The details of how genetic variation contributes to variable symptomatology are unclear, creating a major challenge for translating vast amounts of data into clinically-useful information. To determine if variation in ASD risk genes correlates with symptomatology differences among individuals with ASD, thus informing treatment, we developed an approach to calculate the likelihood of genetic dysfunction in Gene Ontology-defined biological processes that have significant overrepresentation of known risk genes. Using whole-exome sequence data from 2,381 individuals with ASD included in the Simons Simplex Collection, we identified likely damaging variants and conducted a clustering analysis to define subgroups based on scores reflecting genetic dysfunction in each process of interest to ASD etiology. Dysfunction in cognition-related genes distinguished a distinct subset of individuals with increased social deficits, lower IQs, and reduced adaptive behaviors when compared to individuals with no evidence of cognition-related gene dysfunction. In particular, a stop-gain variant in the pharmacogene encoding cycloxygenase-2 was associated with having an IQ<70 (i.e. intellectual disability), a key comorbidity in ASD. We expect that screening genes involved in cognition for deleterious variants in ASD cases may be useful for identifying clinically-informative factors that should be prioritized for functional follow-up. This has implications in designing more comprehensive genetic testing panels and may help provide the basis for more informed treatment in ASD.