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Open Access Publications from the University of California

Genomic Patterns of De Novo Mutation in Simplex Autism.

  • Author(s): Turner, Tychele N
  • Coe, Bradley P
  • Dickel, Diane E
  • Hoekzema, Kendra
  • Nelson, Bradley J
  • Zody, Michael C
  • Kronenberg, Zev N
  • Hormozdiari, Fereydoun
  • Raja, Archana
  • Pennacchio, Len A
  • Darnell, Robert B
  • Eichler, Evan E
  • et al.

To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10-8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10-3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10-3), suggesting a path forward for genetically characterizing more complex cases of autism.

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