Global increases in both common and rare copy number load associated with autism

Childrenwith autismhave an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical develop-ment from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regionsflankedbysegmental duplications (genomichotspots) for events>50 kbp and the entire genomic backbone for variants>300 kbp using a custom targeted DNA microarray. This analysis was comple-mented by a separate study of five highly dynamic hotspots associated with autism or developmental delay syn-dromes, using a finely tiled array platform (>1 kbp) in 142 children matched for gender and ethnicity. In both studies, a significant increase in the number of base pairs of duplication, but not deletion, was associated with autism. Significantly elevated levels of CNV load remained after the removal of rare and likely pathogeni