Background Autism Spectrum Disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. ASD-associated variants range from changes to a Single Base Pair (SNPs), to the loss or gain of multiple base pairs (Copy Number Variants, CNVs). In addition, ASD-associated variants can be either inherited or de-novo, and either common, with a small increase to risk, or rare, with a strong causal effect. Identifying a set of individuals with greater phenotypic homogeneity may help us reduce genetic heterogeneity, and pinpoint mutations that give us greater insight into the genetic roots of the entire autism spectrum. Under this hypothesis, the Perelman School of Medicine at the University of Pennsylvania established ASPE, the Asperger Syndrome/Autism Spectrum (AS/ASD) Program of Excellence, in 2017, to significantly improve the understanding of the genetic causes of AS/ASD. A major focus of ASPE will be on the NRXN1 gene, which codes for the protein neurexin 1 and has been associated with Autism Spectrum Disorder and other psychiatric and neurodevelopmental disorders. Methods The team will compare the genomes of individuals with and without mutations in the NRXN1 gene and individuals with AS and their family members who may or may not have been diagnosed with AS. We hypothesized that risk for ASD is the result of a cumulative effect of common, small effect variants with additional strong contributions to risk arising from rare, severe effect mutations in genes such as NRXN1. As an initial exploration of this hypothesis, we utilized publically available genotype and exome sequence data (Autism Genetic Resource Exchange, Simons Simplex Collection) and summary statistics from a recent autism GWAS (Psychiatric Genomics Consortium: ASD) to generate polygenic risk scores for all individuals within a family, and establish the contribution of common variants to ASD risk. In addition, we identified rare damaging mutations (both SNPs and CNVs) in genes previously associated with ASD, including NRXN1. Results Common polygenic risk for ASD varies between families with an ASD proband, with some families carrying high risk for ASD, and others carrying low risk. Risk scores in the ASD probands are significantly higher than unaffected family members. We identified several families with low risk for ASD that carry a mutation in NRXN1, suggesting that some individuals will develop ASD as a result of common variation, whereas others with low common polygenic risk may develop ASD as a result of a severe effect variant. Discussion Overall, our findings show that it is necessary to explore the mutational spectrum of variants in families by including both common and rare SNPs and CNVs, to fully capture the genetic basis of risk for ASD.