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

Hrishikesh Chakraborty,Julia L. Sharp,Emily L. Casanova,Manuel F. Casanova,Nahid Sultana Sumi

doi:10.1186/s13229-016-0082-z

Hrishikesh Chakraborty, Julia L. Sharp

Open Access

https://doi.org/10.1186/s13229-016-0082-z

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Abstract

BackgroundIntellectual 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.MethodsUtilizing 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.ResultsThe 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.ConclusionsAccording 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-016-0082-z) contains supplementary material, which is available to authorized users.

Highlights

Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another
Comorbidity data We studied the comorbidities of a substantial list of IDs with known molecular origins derived from the Mendelian Inheritance in Man (MIM) database
55 % (N = 116) of autism-related conditions listed epilepsy as a common feature, which was consistent across both highly comorbid autism (HCA) and variable autism (VarAut) groups, reinforcing ideas of their shared etiologies (Table 1)

Summary

Introduction

Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. Intellectual disability (ID), epilepsy, and autism are highly comorbid with one another, suggesting shared etiologies in at least some forms of these conditions. In both autism and ID, epilepsy occurs in approximately one-third of cases, respectively [1, 2]. About 31 % of autistic children aged 8 have IQs within the ID range, and an additional 23 % fall within the borderline region [4] These high comorbidity rates stress an etiological commonality among some forms of the conditions, though it leaves unanswered the question of which forms are more susceptible to co-occurrence. Popular foci of study include monogenic syndromes such as tuberous sclerosis (TSC), fragile X

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