The Genetics of Autism: Key Issues, Recent Findings, and Clinical Implications

There is credible evidence that environmental factors influence individual risk and/or severity of autism spectrum disorders (hereafter referred to as autism). While it is likely that environmental chemicals contribute to the etiology of autism via multiple mechanisms, identifying specific environmental factors that confer risk for autism and understanding how they contribute to the etiology of autism has been challenging, in part because the influence of environmental chemicals likely varies depending on the genetic substrate of the exposed individual. Current research efforts are focused on elucidating the mechanisms by which environmental chemicals interact with autism genetic susceptibilities to adversely impact neurodevelopment. The goal is to not only generate insights regarding the pathophysiology of autism, but also inform the development of screening platforms to identify specific environmental factors and gene × environment (G × E) interactions that modify autism risk. Data from such studies are needed to support development of intervention strategies for mitigating the burden of this neurodevelopmental condition on individuals, their families and society. In this review, we discuss environmental chemicals identified as putative autism risk factors and proposed mechanisms by which G × E interactions influence autism risk and/or severity using polychlorinated biphenyls (PCBs) as an example.

BK K⁺ channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the KCNMA1 gene and cell- and tissue-selective β subunits (KCNMB1-4). Mutations in KCNMA1 are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology. The β2 subunit is expressed in central neurons and imparts inactivation to BK channels, as well as altering activation and deactivation gating. In this study, we report the functional effect of G124R, a novel KCNMB2 mutation obtained from whole-exome sequencing of a patient diagnosed with autism spectrum disorder. Residue G124, located in the extracellular loop between TM1 and TM2, is conserved across species, and the G124R missense mutation is predicted deleterious with computational tools. To investigate the pathogenicity potential, BK channels were co-expressed with β2^WT and β2^G124R subunits in HEK293T cells. BK/β2 currents were assessed from inside-out patches under physiological K⁺ conditions (140/6 mM K⁺ and 10 μM Ca²⁺) during activation and inactivation (voltage-dependence and kinetics). Using β2 subunits lacking inactivation (β2IR) revealed that currents from BK/β2IR^G124R channels activated 2-fold faster and deactivated 2-fold slower compared with currents from BK/β2IR^WT channels, with no change in the voltage-dependence of activation (V_1/2). Despite the changes in the BK channel opening and closing, BK/β2^G124R inactivation rates (τ_inact and τ_recovery), and the V_1/2 of inactivation, were unaltered compared with BK/β2^WT channels under standard steady-state voltage protocols. Action potential-evoked current was also unchanged. Thus, the mutant phenotype suggests the β2^G124R TM1-TM2 extracellular loop could regulate BK channel activation and deactivation kinetics. However, additional evidence is needed to validate pathogenicity for this patient-associated variant in KCNMB2.

Background: Developmental disabilities have been largely studied in the past years. Their etiological mechanisms have been underpinned to the interactions between genetic and environmental factors. These factors show variability across the world. Thus, it is important to understand where the set of knowledge obtained on developmental disabilities originates from and whether it is generalizable to low- and middle-income countries. Aims: This study aims to understand the origins of the available literature on developmental disabilities, keeping a focus on parenting, and identify the main trend of research. Methods and Procedure: A sample of 11,315 publications from 1936 to 2020 were collected from Scopus and a graphical country analysis was conducted. Furthermore, a qualitative approach enabled the clustering of references by keywords into four main areas: “Expression of the disorder”, “Physiological Factors”, “How it is studied” and “Environmental factors”. For each area, a document co-citation analysis (DCA) on CiteSpace software was performed. Outcomes and Results: Results highlight the leading role of North America in the study of developmental disabilities. Trends in the literature and the documents’ scientific relevance are discussed in details. Conclusions and Implications: Results demand for investigation in different socio-economical settings to generalize our knowledge.

What this paper adds?

The current paper tries to provide insight into the origins of the literature on developmental disabilities with a focus on parenting, together with an analysis of the trends of research in the field. The paper consisted of a multi-disciplinary and multi-method review. In fact, the review tried to integrate the analysis of the relation between developmental disabilities with a closer look at the scientific contributions to the field across the world. Specifically, the paper integrates a total of 11,315 papers published on almost a century of research (from 1936 to 2020). An initial qualitative analysis on keywords was combined to a subsequent quantitative approach in order to maximize the comprehension of the impact of almost a century of scientific contributions. Specifically, documents were studied with temporal and structural metrics on a scientometric approach. This allowed the exploration of patterns within the literature available on Scopus in a quantitative way. This method not only assessed the importance of single documents within the network. As a matter of fact, the document co-citation analysis used on CiteSpace software provided insight into the relations existing between multiple documents in the field of research. As a result, the leading role of North America in the literature of developmental disabilities and parenting emerged. This was accompanied by the review of the main trends of research within the existing literature.

Dendritic spines are small actin-rich protrusions from neuronal dendrites that form the postsynaptic part of most excitatory synapses. Changes in the shape and size of dendritic spines correlate with the functional changes in excitatory synapses and are heavily dependent on the remodeling of the underlying actin cytoskeleton. Recent evidence implicates synapses at dendritic spines as important substrates of pathogenesis in neuropsychiatric disorders, including autism spectrum disorder (ASD). Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of the spine and synapse pathology may provide insight into their etiologies and could reveal new drug targets. In this review, we will discuss recent findings of defective actin regulation in dendritic spines associated with ASD.