Genomic architecture of autism from comprehensive whole-genome sequence annotation

Cell. 2022 Nov 10;185(23):4409-4427.e18. doi: 10.1016/j.cell.2022.10.009.


Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Keywords: autism spectrum disorder; copy-number variation; neurodevelopmental disorders; phenotype measures; polygenic risk scores; rare variants; structural variation; whole-genome sequencing.

Publication types

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

MeSH terms

  • Autism Spectrum Disorder* / genetics
  • Autistic Disorder*
  • DNA Copy Number Variations / genetics
  • Genetic Predisposition to Disease
  • Genomics
  • Humans