WHOLE TRANSCRIPTOME ANALAYSIS BY NEXT GENERATION SEQUENCING (NGS) IN AUTISM SPECTRUM DISORDERS (ASDs)

Autism Spectrum Disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviours. Evidences indicate that ASDs have strong genetic bases. Known chromosomal anomalies, rare genetic variants and single nucleotide polymorphisms (SNPs) have been related to ASD phenotypes in many studies. Furthermore Comparative Genomic Hybridization (CGH) studies have revealed copy number variations (CNVs) as risk factors. Recently, several studies have suggested that lymphoblastoid cells (LCLs) can discriminate between ASDs and control samples. This study is part of a Telethon project which has been started in 2009 and involves different Italian clinical and research groups; it aims to analyze gene expression variations in ASD subjects, characterized for CNVs potentially involved in the onset of autism. Transcriptome from LCLs of 27 ASD probands and 23 health controls have been analyzed through Next Generation Sequencing technology (RNA Sequencing). Gene set enrichment analysis (GSEA), on the total cohort and on a subgroup with a 22q13.3 deletion, revealed that autoimmune disorders and antigen processing and presentation pathways are the most enriched ones. Subgroup’s GSEA highlights the involvement of axon guidance pathway, confirming that LCLs could exhibit biomarkers relevant to autism. Moreover, we demonstrate that three outlier genes cluster within a CNV on 16p13.1, suggesting that this is a potential candidate ASD region. This study provides evidence that potentially causative structural variants have a functional impact via transcriptome alterations in ASDs at a genome wide level and demonstrates the utility of integrating gene expression with mutation data. Further analysis of differentially expressed genes and CNVs not selected in this study will help understanding the genetic bases for ASD pathophysiology and unravelling potential new pathways involved in ASDs.