Abstract
We have used Gene Ontology (GO) and pathway analyses to uncover the common functions associated to the genes overlapping Copy Number Variants (CNVs) in autistic patients. Our source of data were four published studies [1-4]. We first applied a two-step enrichment strategy for autism-specific genes. We fished out from the four mentioned studies a list of 2928 genes overall overlapping 328 CNVs in patients and we first selected a sub-group of 2044 genes after excluding those ones that are also involved in CNVs reported in the Database of Genomic Variants (enrichment step 1). We then selected from the step 1-enriched list a sub-group of 514 genes each of which was found to be deleted or duplicated in at least two patients (enrichment step 2). The number of statistically significant processes and pathways identified by the Database for Annotation, Visualization and Integrated Discovery and Ingenuity Pathways Analysis softwares with the step 2-enriched list was significantly higher compared to the step 1-enriched list. In addition, statistically significant GO terms, biofunctions and pathways related to nervous system development and function were exclusively identified by the step 2-enriched list of genes. Interestingly, 21 genes were associated to axon growth and pathfinding. The latter genes and other ones associated to nervous system in this study represent a new set of autism candidate genes deserving further investigation. In summary, our results suggest that the autism’s “connectivity genes” in some patients affect very early phases of neurodevelopment, i.e., earlier than synaptogenesis.
Highlights
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders that affects approximately 1 in 150 individuals and are characterized by deficits in reciprocal social interaction, communication and patterns of repetitive behaviours and restricted interests [5]
Our metaanalysis was based on three assumptions: (i) the number of autism susceptibility genes overlapping Copy Number Variants (CNVs) detected on a single patient may be insufficient to recover significant information in functional annotation analyses, (ii) only a subset of all genes overlapping a “pathogenic” or “potentially pathogenic” CNV would be linked to autism, (iii) several duplicated or deleted genes from different CNVs and patients may participate to the same pathogenic mechanism
Gene Ontology (GO) and IPA analyses have provided several lines of evidences that our two-step enrichment strategy has generated a set of genes (CS2 = 514 genes) many of which are probably related to nervous system development and function suggesting their relation to autism’s etiology
Summary
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders that affects approximately 1 in 150 individuals and are characterized by deficits in reciprocal social interaction, communication and patterns of repetitive behaviours and restricted interests [5]. These “core deficits” can be variable among patients as far their severity and time of onset is concerned. Non-core symptoms (mental retardation, epilepsy, gastro-intestinal disturbances, macrocephaly etc.), are observed only in subgroups of patients This remarkable phenotypic complexity probably underlies multiple etiologies assumed to disrupt one or more phases of neurodevelopment. These studies have led to the identification of several loci implicated in ASDs etiology
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