Postzygotic single-nucleotide mosaicisms contribute to the etiology of autism spectrum disorder and autistic traits and the origin of mutations

Hum Mutat. 2017 Aug;38(8):1002-1013. doi: 10.1002/humu.23255. Epub 2017 May 30.


The roles and characteristics of postzygotic single-nucleotide mosaicisms (pSNMs) in autism spectrum disorders (ASDs) remain unclear. In this study of the whole exomes of 2,361 families in the Simons Simplex Collection, we identified 1,248 putative pSNMs in children and 285 de novo SNPs in children with detectable parental mosaicism. Ultra-deep amplicon resequencing suggested a validation rate of 51%. Analyses of validated pSNMs revealed that missense/loss-of-function (LoF) pSNMs with a high mutant allele fraction (MAF≥ 0.2) contributed to ASD diagnoses (P = 0.022, odds ratio [OR] = 5.25), whereas missense/LoF pSNMs with a low MAF (MAF<0.2) contributed to autistic traits in male non-ASD siblings (P = 0.033). LoF pSNMs in parents were less likely to be transmitted to offspring than neutral pSNMs (P = 0.037), and missense/LoF pSNMs in parents with a low MAF were transmitted more to probands than to siblings (P = 0.016, OR = 1.45). We estimated that pSNMs in probands or de novo mutations inherited from parental pSNMs increased the risk of ASD by approximately 6%. Adding pSNMs into the transmission and de novo association test model revealed 13 new ASD risk genes. These results expand the existing repertoire of genes involved in ASD and shed new light on the contribution of genomic mosaicisms to ASD diagnoses and autistic traits.

Keywords: autism spectrum disorder; autistic traits; parental mosaicism; single-nucleotide mosaicism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Autism Spectrum Disorder / etiology*
  • Autism Spectrum Disorder / genetics*
  • Autistic Disorder / etiology*
  • Autistic Disorder / genetics*
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Male
  • Mosaicism
  • Mutation
  • Polymorphism, Single Nucleotide / genetics*