Large mosaic copy number variations confer autism risk

Although germline de novo copy number variants are a known cause of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. Here, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 ASD probands and 5,500 unaffected siblings in the Simons Simplex Collection (SSC) and Simons Powering Autism Research for Knowledge (SPARK) cohorts. We detected 46 mCNVs in probands and 19 mCNVs in siblings ranging from 49 kb to 249 Mb and affecting 2.8-73.8% of cells. In both cohorts, probands carried a significant burden of large (>4 Mb) mCNVs (P = 0.043 and P = 6.6 × 10−3 in SSC and SPARK, respectively), which were present in a total of 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5-84.2). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD. Event size positively correlated with severity of ASD symptoms (P = 0.016), and four probands exhibited clinical symptoms consistent with syndromes previously associated with genes or regions disrupted by their respective mosaic mutations. In analyses of post-mortem brain tissue from 60 additional probands, we further detected and experimentally validated two mCNVs including a complex 10.3 Mb duplication on chromosome 2. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.