Large mosaic copy number variations confer autism risk.

Abstract

Although germline de novo copy number variants are known causes 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. We detected 46 mCNVs in probands and 19 mCNVs in siblings affecting 2.8–73.8% of cells. Probands carried a significant burden of large (>4 Mb) mCNVs, which were detected in 25 probands but only 1 sibling (OR=11.4, 95% CI=1.5–84.2, P=7.4×10−4). Event size positively correlated with severity of ASD symptoms (P=0.016). Surprisingly, we did not observe mosaic analogues of the short de novo CNVs recurrently observed in ASD (e.g. 16p11.2). We further experimentally validated two mCNVs in post-mortem brain tissue from 59 additional probands. These results indicate that mosaic CNVs contribute a previously unexplained component of ASD risk.