ELMOD3-SH2D6 gene fusion as a possible co-star actor in autism spectrum disorder scenario.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by high heritability. It is known that genetic factors contribute to ASD pathogenesis. In particular, copy number variants (CNVs) are involved in ASD susceptibility and can affect gene expression regulation. 2p11.2 microdeletions encompassing ELMOD3, CAPG and SH2D6 genes have been described in four unrelated ASD families. The present study revealed that this microdeletion is responsible for the production of a chimeric transcript generated from the fusion between ELMOD3 and SH2D6. The identified transcript showed significantly higher expression levels in subjects carrying the deletion compared to control subjects, suggesting that it is not subjected to nonsense-mediated decay and might encode for a chimeric protein. In conclusion, this study suggests the possible involvement of this gene fusion, together with the other previously identified variants, in ASD.

An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects social interaction and communication, with restricted interests, activity and behaviors. ASD is highly familial, indicating that genetic background strongly contributes to the development of this condition. However, only a fraction of the total number of genes thought to be associated with the condition have been discovered. Moreover, other factors may play an important role in ASD onset. In fact, it has been shown that parental conditions and in utero and perinatal factors may contribute to ASD etiology. More recently, epigenetic changes, including DNA methylation and micro RNA alterations, have been associated with ASD and proposed as potential biomarkers. This review aims to provide a summary of the literature regarding ASD candidate genes, mainly focusing on synapse formation and functionality and relevant epigenetic and environmental aspects acting in concert to determine ASD onset.

A Statistical Physics Perspective to Understand Social Visual Attention in Autism Spectrum Disorder.

This study investigated social visual attention in children with Autism Spectrum Disorder (ASD) and with typical development (TD) in the light of Brockmann and Geisel's model of visual attention. The probability distribution of gaze movements and clustering of gaze points, registered with eye-tracking technology, was studied during a free visual exploration of a gaze stimulus. A data-driven analysis of the distribution of eye movements was chosen to overcome any possible methodological problems related to the subjective expectations of the experimenters about the informative contents of the image in addition to a computational model to simulate group differences. Analysis of the eye-tracking data indicated that the scanpaths of children with TD and ASD were characterized by eye movements geometrically equivalent to Lévy flights. Children with ASD showed a higher frequency of long saccadic amplitudes compared with controls. A clustering analysis revealed a greater dispersion of eye movements for these children. Modeling of the results indicated higher values of the model parameter modulating the dispersion of eye movements for children with ASD. Together, the experimental results and the model point to a greater dispersion of gaze points in ASD.

Attention toward Social and Non-Social Stimuli in Preschool Children with Autism Spectrum Disorder: A Paired Preference Eye-Tracking Study.

Different dimensions of visual attention to social (human faces) and non-social stimuli (objects) were assessed in 19 preschool children with Autism Spectrum Disorder (ASD) and 19 typically developing (TD) age, gender, and IQ-matched controls through an original paired preference eye-tracking paradigm. The present study found a significantly reduced attentional bias toward human faces in children with ASD compared to TD controls. The analysis of the total fixation time showed a significantly reduced preference for faces in children with ASD compared to TD children. Moreover, while TD children showed a significant preference for the face over the object, children in the ASD group observed the two paired pictures for a similar amount of time, thus showing no preference. Besides, children with ASD paid significantly more sustained attention to the objects than TD children. Children in the TD group paid greater sustained attention to the faces over the objects, while children in the ASD group did not differentiate between objects and faces. Finally, an age effect was found in ASD, as younger children in the group tended to prefer objects and to show more sustained attention towards them. Overall, these findings add to the literature on anomalies in attention toward social and non-social stimuli in young children with ASD compared to their TD counterparts. These results are discussed in the light of previous studies and suggest possible directions for future research.

Digit-tracking as a new tactile interface for visual perception analysis.

Eye-tracking is a valuable tool in cognitive science for measuring how visual processing resources are allocated during scene exploration. However, eye-tracking technology is largely confined to laboratory-based settings, making it difficult to apply to large-scale studies. Here, we introduce a biologically-inspired solution that involves presenting, on a touch-sensitive interface, a Gaussian-blurred image that is locally unblurred by sliding a finger over the display. Thus, the user's finger movements provide a proxy for their eye movements and attention. We validated the method by showing strong correlations between attention maps obtained using finger-tracking vs. conventional optical eye-tracking. Using neural networks trained to predict empirically-derived attention maps, we established that identical high-level features hierarchically drive explorations with either method. Finally, the diagnostic value of digit-tracking was tested in autistic and brain-damaged patients. Rapid yet robust measures afforded by this method open the way to large scale applications in research and clinical settings.

Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, a gene intolerant to loss of function mutation, encoding for a voltage-dependent anion channel localized on PSD. Moreover, four missense damaging variants were identified in genes intolerant to loss of function variation encoding for PSD proteins: PLXNA2, KCTD16, ARHGAP21, and SLC4A1. This study identifies CAPG and VDAC3 as candidate genes and provides additional support for genes encoding PSD proteins in ASD susceptibility.

Impaired representational gaze following in children with autism spectrum disorder.

Using eye-tracking methodology, we compared spontaneous gaze following in young children with Autism Spectrum Disorder (mean age 5.8 years) to that of typically developing children (mean age 5.7 years). Participants saw videos in which the position of a hidden object was either perceptually visible or was only represented in another person's mind. The findings indicate that children with Autism Spectrum Disorder were significantly less accurate in gaze following and observed the attended object for less time than typically developing children only in the Representational Condition. These results show that children with Autism Spectrum Disorder are responsive to gaze as a perceptual cue although they ignore its representational meaning.

Exploring the Role of Theory of Mind in Moral Judgment: The Case of Children with Autism Spectrum Disorder.

This paper adds to the growing research on moral judgment (MJ) by considering whether theory of mind (ToM) might foster children's autonomous MJ achievement. A group of 30 children with autism spectrum disorder (ASD) was compared in MJ and ToM with 30 typically developing (TD) children. Participants were tested for MJ with a classical Piaget's task and for ToM with a second order False Belief task. In the moral task, children were told two versions of a story: in one version the protagonist acted according to a moral intention but the action resulted in a harmful consequence; in the other version the protagonist acted according to an immoral intention, but the action resulted in a harmless consequence. Children were asked which of the two protagonists was the "naughtier." In line with previous studies, the results indicated that, while the majority of TD participants succeeded in the second order False Belief task, only few individuals with ASD showed intact perspective taking abilities. The analysis of the MJ in relation to ToM showed that children with ASD lacking ToM abilities judged guilty the protagonists of the two versions of the story in the moral task because both of them violated a moral rule or because they considered the consequences of the actions, ignoring any psychological information. These results indicate a heteronomous morality in individuals with ASD, based on the respect of learned moral rules and outcomes rather than others' subjective states.

Oxytocin and autism: a systematic review of randomized controlled trials.

OBJECTIVE: Little is known about the effectiveness of pharmacological interventions on autism spectrum disorder (ASD). This is a systematic review of the randomized controlled trials (RCTs) of oxytocin interventions in autism, made from January 1990 to September 2013. METHOD: A search of computerized databases was supplemented by manual search in the bibliographies of key publications. The methodological quality of the studies included in the review was evaluated independently by two researchers, according to a set of formal criteria. Discrepancies in scoring were resolved through discussion. RESULTS: The review yielded seven RCTs, including 101 subjects with ASD (males=95) and 8 males with Fragile X syndrome. The main categories of target symptoms tested in the studies were repetitive behaviors, eye gaze, and emotion recognition. The studies had a medium to high risk of bias. Most studies had small samples (median=15). All the studies but one reported statistically significant between-group differences on at least one outcome variable. Most findings were characterized by medium effect size. Only one study had evidence that the improvement in emotion recognition was maintained after 6 weeks of treatment with intranasal oxytocin. Overall, oxytocin was well tolerated and side effects, when present, were generally rated as mild; however, restlessness, increased irritability, and increased energy occurred more often under oxytocin. CONCLUSIONS: RCTs of oxytocin interventions in autism yielded potentially promising findings in measures of emotion recognition and eye gaze, which are impaired early in the course of the ASD condition and might disrupt social skills learning in developing children. There is a need for larger, more methodologically rigorous RCTs in this area. Future studies should be better powered to estimate outcomes with medium to low effect size, and should try to enroll female participants, who were rarely considered in previous studies. Risk of bias should be minimized. Human long-term administration studies are necessary before clinical recommendations can be made.