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Gene discoveries in autism are biased towards comorbidity with intellectual disability
  1. Matthew Jensen,
  2. Corrine Smolen,
  3. Santhosh Girirajan
  1. Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA
  1. Correspondence to Dr Santhosh Girirajan, Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA; sxg47{at}


Background Autism typically presents with highly heterogeneous features, including frequent comorbidity with intellectual disability (ID). The overlap between these phenotypes has confounded the diagnosis and discovery of genetic factors associated with autism. We analysed pathogenic de novo genetic variants in individuals with autism who had either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity.

Methods We analysed 2290 individuals from the Simons Simplex Collection for de novo likely gene-disruptive (LGD) variants and copy-number variants (CNVs), and determined their relevance towards IQ and Social Responsiveness Scale (SRS) measures.

Results Individuals who carried de novo variants in a set of 173 autism-associated genes showed an average 12.8-point decrease in IQ scores (p=5.49×10−6) and 2.8-point increase in SRS scores (p=0.013) compared with individuals without such variants. Furthermore, individuals with high-functioning autism (IQ >100) had lower frequencies of de novo LGD variants (42 of 397 vs 86 of 562, p=0.021) and CNVs (9 of 397 vs 24 of 562, p=0.065) compared with individuals who manifested both autism and ID (IQ <70). Pathogenic variants disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID, while de novo variants observed in individuals with high-functioning autism disrupted genes with little functional relevance towards neurodevelopment.

Conclusions Pathogenic de novo variants disrupting autism-associated genes contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

  • autism
  • intellectual disability
  • comorbid features
  • genetic complexity

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  • Contributors MJ and SG conceptualised the study, and MJ and CS analysed the data. MJ and SG wrote the manuscript with input from all authors.

  • Funding This work was supported by NIH R01-GM121907, SFARI Pilot Grant (#399894) and resources from the Huck Institutes of the Life Sciences to SG, and NIH T32-GM102057 to MJ.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval As the data analysed in the study were de-identified, the study was exempt from IRB review. The study conformed to the Helsinki Declaration.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Approved researchers can obtain the SSC data sets described in this study by applying at