Genomic Patterns of De Novo Mutation in Simplex Autism

• Published in: Cell 2017-10, Vol.171 (3), p.710-722.e12
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Animals; attributable fraction; autism; Autistic Disorder - genetics; de novo mutation; DNA Copy Number Variations; DNA Mutational Analysis; Female; genome sequencing; Genome-Wide Association Study; Humans; INDEL Mutation; Male; mechanisms of disease; Mice; multifactorial genetics; noncoding; oligogenic; Polymorphism, Single Nucleotide; regulatory
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.08.047

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. [Display omitted] •Comprehensive CNV/SNV dataset from whole-genome sequencing of 516 autism families•Estimated human germline mutation rate of ∼1.5 × 10−8 substitutions/site/generation•Autism probands enriched for de novo missense, promoter, and enhancer mutations•Oligogenic de novo mutation signals for genes enriched in striatal neuron expression Genomic analysis of 516 families with an autistic child and an unaffected sibling suggests that simplex autism results from de novo mutation and is oligogenic.