Abstracts

Rationale: Epilepsy and Autism have been estimated to coexist in around 20-30% of the patients with either disorder. Early onset seizures in infants have also been associated with a future risk of autism. The wide prevalence and association of these two disorders suggest common genetic factors and pathway correlations along with an increased predisposition for other pathologies. Lack of evidence-based recommendations for people afflicted by both these disorders suggest that insights into the common genetic ground of both these disorders is needed. Methods: Electronic medical records of University of Louisville and Vanderbilt, of pediatric patients who had had a primary diagnosis of both Epilepsy and Autism, not secondary to an existing disorder or syndrome were searched. 57 subjects had genomic data available in the form of pathogenic Copy Number Variants (CNV). Genes present in the affected chromosomal loci (370 genes) of subjects were identified. Pathway data was derived from genes from autism and epilepsy subjects, and 2100+ sequencing genes having links to neurological and developmental abnormalities, a total of 2470+ genes. Gene-set enrichment analysis using the Wikipathways Pathway database from WebGestalt was performed to derive pathway networks. Protein-protein interaction analyses using STRING at a confidence level of 0.70 (high) were performed and we further analyzed these genes for their mRNA co-expression using genenetwork.org. Gene-set enrichment analyses using the Phenotype and the PheWas Analysis databases (WebGestalt) were performed to derive phenotypic correlations and disease associations. Results: Wikipathways Pathway database analyses resulted in a network of 60 pathways. Genes from the subject database were mapped onto this network resulting in 53 pathways that had 28 genes from 13 unique patients. The most prominent pathways that featured in the subject database with respect to the number of patient genes involved in them and their P values were the MAPK signaling pathway (adjusted P value = 3.86e-05), Calcium regulation in the cardiac cell (adjusted P value=3.86e-05), Physiological and pathological hypertrophy of the heart (adjusted P value= 3.09e-05), Hepatocyte growth factor receptor signaling (adjusted P value=3.86e-05) and IL-3 signaling (adjusted P value = 4.86e-05). Other major pathways identified include- microRNAs in cardiac hypertrophy, TNF alpha signaling pathway, G protein signaling, Oncostatin M signaling, B cell receptor signaling pathway, IL-2 and IL-5 signaling pathways, EGF-EGFR signaling, and Biogenic Amine synthesis. Protein-protein interaction using STRING at a confidence level of 0.70 (high) resulted in a list of 15 genes, which were further analyzed for their mRNA co-expression revealing a group of 10 genes that were co-expressed. Phenotype and PheWas analyses revealed their associations with Endocrine disorders (hypoparathyroidism), Immune pathologies (aplasia/hypoplasia of the thymus), Musculoskeletal dysplasia (Radial deviation of the hand), and Cardiac dysrhythmias (Atrial fibrillation/flutter). Conclusions: The genomic architecture of autism and epilepsy patients with CNVs suggest that small subset of genes may play a dominant role in pathways and clinical expression of endophenotypes within this subgroup. Further research is needed to determine if this mechanism applies across other populations of autism and epilepsy subjects. Funding: No funding received.