Variation in Gene Expression in Autism Spectrum Disorders: An Extensive Review of Transcriptomic Studies

Abstract

Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental conditions that present in early childhood and have a current estimated prevalence of about 1 in 68 US children, 1 in 42 boys. ASDs are heterogeneous, and arise from epigenetic, genetic and environmental origins, yet, the exact etiology of ASDs still remains unknown. Individuals with ASDs are characterized by having deficits in social interaction, impaired communication and a range of stereotyped and repetitive behaviors. Currently, a diagnosis of ASD is based solely on behavioral assessments and phenotype. Hundreds of diverse ASD susceptibility genes have been identified, yet none of the mutations found account for more than a small subset of autism cases. Therefore, a genetic diagnosis is not yet possible for the majority of the ASD population. The susceptibility genes that have been identified are involved in a wide and varied range of biological functions. Since the genetics of ASDs is so diverse, information on genome function as provided by transcriptomic data is essential to further our understanding. Gene expression studies have been extremely useful in comparing groups of individuals with ASD and control samples in order to measure which genes (or group of genes) are dysregulated in the ASD group. Transcriptomic studies are essential as a key link between measuring protein levels and analyzing genetic information. This review of recent autism gene expression studies highlights genes that are expressed in the brain, immune system, and processes such as cell metabolism and embryology. Various biological processes have been shown to be implicated with ASD individuals as well as differences in gene expression levels between different types of biological tissues. Some studies use gene expression to attempt to separate autism into different subtypes. An updated list of genes shown to be significantly dysregulated in individuals with autism from all recent ASD expression studies will help further research isolate any patterns useful for diagnosis or understanding the mechanisms involved. The functional relevance of transcriptomic studies as a method of classifying and diagnosing ASD cannot be underestimated despite the possible limitations of transcriptomic studies.

Single-cell RNA sequencing of a European and an African lymphoblastoid cell line

“…LCLs are also an in vitro model system for a variety of molecular and functional assays, contributing to studies in immunology, cellular biology, genetics, and many other research areas 6-12 . It is also believed that gene expression in LCLs encompasses a wide range of metabolic pathways specific to individuals where the cells originated 13 .…”

Multifarious Functions of the Fragile X Mental Retardation Protein

“…FMRP selectively associates with a subset of mRNAs: the candidate target list is long, but altered protein levels have been established for only a tiny handful of proteins (Table 2) [29,31]. Indeed, proteomic screens suggest that the number of protein changes in both mouse and Drosophila FXS models is surprisingly small, and many of these changes may be indirect, since they don’t align well with mRNA-binding data [32]. Given synaptic defects in FXS patients and models, there is a particular bias towards mRNA targets encoding synaptic proteins [33].…”

“…FMRP also binds signaling proteins, including Janus kinase and microtubule interacting protein 1 (JAKMIP1) and cytoplasmic FMR1 interaction protein 1 (CYFIP1 ; Table 3). A recent gene expression study shows JAKMIP1 modulates microtubule transport and GABA B R levels [32]. WAVE complex CYFIP1 links FMRP to actin regulation, and mechanistic target of rapamycin (mTor) signaling in both mice and Drosophila [45].…”

A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood

“…Postmortem brain gene expression studies have guided understanding of ASD pathophysiology and show evidence of changes in gene co-expression and enrichment in immune response and neuronal activity functions [5,6]. Peripheral blood gene expression studies in children and adults using whole blood and in specific cell types (natural killer (NK) cell and lymphocytes) observed enrichment of immune and inflammatory processes in differential gene expression associated with ASD [7,8]. Recent efforts have been focused on identifying how genetic risk factors converge into one or more unifying pathways and pathophysiological mechanisms [9,10].…”