Otizm spektrum bozukluğuna sahip çift yumurta ikizleri ve ailelerinin kapsamlı transkriptom analizi

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social skills, repetitive behaviors, abnormality of speech, and nonverbal communication. ASD has high heritability, however, understanding the complexity of the underlying genetic basis has proven to be a challenging task. We hypothesized that dissecting the aberrations in alternative splicing (AS) and their effects on expression networks might provide insight. Therefore, we performed combinatorial transcriptome analysis, by AS and co-expression analysis of total RNA isolated from Peripheral Blood Mononuclear Cells (PBMCs). In order to minimize effects of genetic background, we employed a twin-based family design, where two pairs of non-syndromic autistic dizygotic (DZ) twins and their parents were analyzed. We identified 183 differential AS events in 146 genes, seven of them being Simons Foundation Autism Research Initiative (SFARI) Category 1-3 genes, namely CUL3, APH1A, PPFIA1, PTPRC, ARID2, PTK7, and DMXL2, strikingly the first three being previously reported to be alternatively-spliced in ASD post-mortem brains. Gene co-expression analysis identified 7 modules with 513 genes, 21 of which were SFARI genes and 5 were differentially alternatively spliced (DAS) genes. Five of these 21 SFARI genes were either Category 1 (ADNP and NR4A2) or Category 2 (DIP2A, PYHIN1, and RAB43). Among five DAS genes within the modules, ZNF322 and NR4A1 could be potentially interesting targets for further investigations, as they display differential AS, have a central role in their networks, and were previously implicated in ASD or brain development. Briefly, our results may be a complementary approach to the current omic-based approaches with practical benefits of the combined analysis of blood transcriptome.