Pathway-based analysis of CNVs is fraught with difficulty (Webber, 2011). However, some patterns have emerged and are becoming increasingly difficult to dismiss. Glessner et al. (2009) observed an enrichment of CNVs at multiple sites, and some of their top hits were genes involved in ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40. Pinto et al. (2010) observed an enrichment of CNVs within gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signaling. Gilman et al. (2011) found an enrichment of CNVs in gene sets related to synapse development, axon targeting, and neuron motility. Although synaptic proteins and ubiquitin pathways were already implicated in ASDs based on small-scale studies (Bourgeron, 2009; Ehlers, 2003), these results suggest that the diversity of rare mutations in ASD affect larger sets of functionally-related genes.
