Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression

Mol Autism. 2016 Mar 15;7:18. doi: 10.1186/s13229-016-0082-z. eCollection 2016.


Background: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities.

Methods: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk.

Results: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS.

Conclusions: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions.

Keywords: Body patterning; Chromatin assembly and disassembly; Epigenomics; Epilepsy; Mental retardation; Regulation of gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Autism Spectrum Disorder / epidemiology
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / psychology
  • Autistic Disorder / epidemiology
  • Autistic Disorder / genetics*
  • Autistic Disorder / psychology
  • Body Patterning / genetics
  • Cell Nucleus / metabolism*
  • Chromatin Assembly and Disassembly / genetics
  • Comorbidity
  • Databases, Genetic
  • Epigenomics
  • Epilepsy / epidemiology
  • Epilepsy / genetics*
  • Epilepsy / psychology
  • Gene Expression Regulation*
  • Gene Ontology*
  • Genetic Association Studies*
  • Humans
  • Intellectual Disability / epidemiology
  • Intellectual Disability / genetics*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Neurogenesis / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Penetrance*
  • Protein Interaction Maps / genetics
  • Risk
  • Syndrome


  • Nerve Tissue Proteins
  • Nuclear Proteins