Large mosaic copy number variations confer autism risk

Maxwell A Sherman; Rachel E Rodin; Giulio Genovese; Caroline Dias; Alison R Barton; Ronen E Mukamel; Bonnie Berger; Peter J Park; Christopher A Walsh; Po-Ru Loh

doi:10.1038/s41593-020-00766-5

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.

Authors

Maxwell A Sherman^{1

2

3}, Rachel E Rodin⁴, Giulio Genovese^{5

6

7}, Caroline Dias^{4

8}, Alison R Barton^{9

5}, Ronen E Mukamel^{9

5}, Bonnie Berger^{10

11}, Peter J Park¹², Christopher A Walsh^{13

14}, Po-Ru Loh^{15

16}

Affiliations

¹ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
⁴ Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Division of Developmental Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹¹ Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹² Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. [email protected].
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹⁴ Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹⁵ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

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

Abstract

Publication types

MeSH terms

Grants and funding