Large mosaic copy number variations confer autism risk

Nat Neurosci. 2021 Feb;24(2):197-203. doi: 10.1038/s41593-020-00766-5. Epub 2021 Jan 11.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autism Spectrum Disorder / epidemiology
  • Autism Spectrum Disorder / genetics*
  • Autopsy
  • Brain Chemistry / genetics
  • Child
  • Child Development Disorders, Pervasive / genetics
  • Cohort Studies
  • DNA Copy Number Variations*
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Mosaicism*
  • Risk Assessment
  • Tissue Banks

Grant support