The Contribution of Mosaic Variants to Autism Spectrum Disorder

PLoS Genet. 2016 Sep 15;12(9):e1006245. doi: 10.1371/journal.pgen.1006245. eCollection 2016 Sep.


De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). We build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex ASD diagnoses (95% credible interval 1.3% to 8.9%). Our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an ASD diagnosis.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Mosaicism*
  • Mutation, Missense
  • Myosin Heavy Chains / genetics*
  • Neoplasm Proteins / genetics*
  • Nonmuscle Myosin Type IIB / genetics*
  • Organ Specificity / genetics
  • Siblings


  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • KMT2D protein, human
  • NCKAP1 protein, human
  • Neoplasm Proteins
  • Nonmuscle Myosin Type IIB
  • nonmuscle myosin type IIB heavy chain
  • Myosin Heavy Chains