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

Abstract

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.

Fig. 1

Gene ontology (GO) term enrichments across groups. a Proportional breakdown of the different comorbidity groups. b Morphogenesis and nervous system-related GO term enrichments according to group. c GO term enrichments in processes related to gene expression regulation by group

Fig. 2

Additional functional and gene ontology (GO) enrichments. a Comparison across groups in number of nuclear epigenetic regulators. b Comparison of GO terms across dominant vs. recessive HCA subgroups. c GO term enrichment across dominant vs. recessive HCE subgroups

Fig. 3

Central nervous system patterning. a String 10 results for general interaction of the core PPI within itself. b General locations of the major embryonic organizing centers of the central nervous system that underlie variations in its dorsoventral and rostrocaudal patterning. c Results across groups for absolute connectivity of experimental proteins to the core PPI network. d Network tightness of proteins surrounding the core PPI network, based upon the average number of intermediary nodes between a target protein and its nearest core PPI neighbor (Figure B adapted from Wurst and Bally-Cuif. Nat Rev Neurosci 2001;2(2):99-108)