Large mosaic copy number variations confer autism risk.
Maxwell A ShermanRachel E RodinGiulio GenoveseCaroline DiasAlison R BartonRonen E MukamelBonnie BergerPeter J ParkChristopher A WalshPo-Ru LohPublished in: Nature neuroscience (2021)
Although germline de novo copy number variants (CNVs) are known causes of autism spectrum disorder (ASD), the contribution of mosaic (early-developmental) copy number variants (mCNVs) has not been explored. In this study, we assessed the contribution of mCNVs to ASD by ascertaining mCNVs in genotype array intensity data from 12,077 probands with ASD 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 one sibling (odds ratio = 11.4, 95% confidence interval = 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 (eg, 16p11.2). We further experimentally validated two mCNVs in postmortem brain tissue from 59 additional probands. These results indicate that mCNVs contribute a previously unexplained component of ASD risk.
Keyphrases
- copy number
- autism spectrum disorder
- intellectual disability
- mitochondrial dna
- attention deficit hyperactivity disorder
- genome wide
- dna methylation
- induced apoptosis
- gene expression
- high throughput
- high resolution
- physical activity
- high intensity
- cell proliferation
- dna repair
- deep learning
- sleep quality
- functional connectivity
- brain injury
- molecular dynamics simulations
- endoplasmic reticulum stress
- signaling pathway