Enhanced segregation of concurrent sounds with similar spectral uncertainties in individuals with autism spectrum disorder.
Ontology highlight
ABSTRACT:
SUBMITTER: Lin IF
PROVIDER: S-EPMC4441195 | biostudies-other | 2015
REPOSITORIES: biostudies-other
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Project description:To assess the clinical impact of splice-altering noncoding mutations in autism spectrum disorder (ASD), we used a deep learning framework (SpliceAI) to predict the splice-altering potential of de novo mutations in 3,953 individuals with ASD from the Simons Simplex Collection. To validate these predictions, we selected 36 individuals that harbored predicted de-novo cryptic splice mutations; each individual represented the only case of autism within their immediate family. We obtained peripheral blood-derived lymphoblastoid cell lines (LCLs) and performed high-depth mRNA sequencing (approximately 350 million 150 bp single-end reads per sample). We used OLego to align the reads against a reference created from hg19 by substituting de novo variants of each individual with the corresponding alternate allele.
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Project description:Adults diagnosed with autism spectrum disorder (ASD) show a reduced sensitivity (degree of selective response) to social stimuli such as human voices. In order to determine whether this reduced sensitivity is a consequence of years of poor social interaction and communication or is present prior to significant experience, we used functional MRI to examine cortical sensitivity to auditory stimuli in infants at high familial risk for later emerging ASD (HR group, N = 15), and compared this to infants with no family history of ASD (LR group, N = 18). The infants (aged between 4 and 7 months) were presented with voice and environmental sounds while asleep in the scanner and their behaviour was also examined in the context of observed parent-infant interaction. Whereas LR infants showed early specialisation for human voice processing in right temporal and medial frontal regions, the HR infants did not. Similarly, LR infants showed stronger sensitivity than HR infants to sad vocalisations in the right fusiform gyrus and left hippocampus. Also, in the HR group only, there was an association between each infant's degree of engagement during social interaction and the degree of voice sensitivity in key cortical regions. These results suggest that at least some infants at high-risk for ASD have atypical neural responses to human voice with and without emotional valence. Further exploration of the relationship between behaviour during social interaction and voice processing may help better understand the mechanisms that lead to different outcomes in at risk populations.
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Project description:Children with autism spectrum disorder (ASD) exhibit difficulties processing and encoding sensory information in daily life. Cognitive response to environmental change in control individuals is naturally dynamic, meaning it habituates or reduces over time as one becomes accustomed to the deviance. The origin of atypical response to deviance in ASD may relate to differences in this dynamic habituation. The current study of 133 children and young adults with and without ASD examined classic electrophysiological responses (MMN and P3a), as well as temporal patterns of habituation (i.e., N1 and P3a change over time) in response to a passive auditory oddball task. Individuals with ASD showed an overall heightened sensitivity to change as exhibited by greater P3a amplitude to novel sounds. Moreover, youth with ASD showed dynamic ERP differences, including slower attenuation of the N1 response to infrequent tones and the P3a response to novel sounds. Dynamic ERP responses were related to parent ratings of auditory sensory-seeking behaviors, but not general cognition. As the first large-scale study to characterize temporal dynamics of auditory ERPs in ASD, our results provide compelling evidence that heightened response to auditory deviance in ASD is largely driven by early sensitivity and prolonged processing of auditory deviance.
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Project description:Maintaining an appropriate distance from others is important for establishing effective communication and good interpersonal relations. Autism spectrum disorder (ASD) is a developmental disorder associated with social difficulties, and it is thus worth examining whether individuals with ASD maintain typical or atypical degrees of social distance. Any atypicality of social distancing may impact daily social interactions. We measured the preferred distances when individuals with ASD and typically developing (TD) individuals approached other people (a male experimenter) and objects (a coat rack with clothes) or when other people approached them. Individuals with ASD showed reduced interpersonal distances compared to TD individuals. The same tendency was found when participants judged their preferred distance from objects. In addition, when being approached by other people, both individuals with ASD and TD individuals maintained larger interpersonal distances when there was eye contact, compared to no eye contact. These results suggest that individuals with ASD have a relatively small personal space, and that this atypicality exists not only for persons but also for objects.
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Project description:BackgroundAutism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder that encompasses a complex and heterogeneous set of traits. Subclinical traits that mirror the core features of ASD, referred to as the broad autism phenotype (BAP), have been documented repeatedly in unaffected relatives and are believed to reflect underlying genetic liability to ASD. The BAP may help inform the etiology of ASD by allowing the stratification of families into more phenotypically and etiologically homogeneous subgroups. This study explores polygenic scores related to the BAP.MethodsPhenotypic and genotypic information were obtained from 2614 trios from the Simons Simplex Collection. Polygenic scores of ASD (ASD-PGSs) were generated across the sample to determine the shared genetic overlap between the BAP and ASD. Maternal and paternal ASD-PGSs were explored in relation to BAP traits and their child's ASD symptomatology.ResultsMaternal pragmatic language was related to child's social communicative atypicalities. In fathers, rigid personality was related to increased repetitive behaviors in children. Maternal (but not paternal) ASD-PGSs were related to the pragmatic language and rigid BAP domains.ConclusionsAssociations emerged between parent and child phenotypes, with more associations emerging in mothers than in fathers. ASD-PGS associations emerged with BAP in mothers only, highlighting the potential for a female protective factor, and implicating the polygenic etiology of ASD-related phenotypes in the BAP.
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Project description:Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic link, but no single well-established cause. This suggests that perturbed regulatory network may better explain its heterogeneity of phenotypes and multiple gene associations. Consistently, our previous study provided evidence of abnormal alternative polyadenylation in transcripts from distinct brain regions suggesting a potential imbalance in the protein synthesis in the postsynaptic density. To test this hypothesis, we studied transcriptome-wide alterations of mRNA translation in post-mortem brain samples from neurotypical and ASD-affected young males subjects. To this end, we employed an optimised polysome profiling technique amendable for small tissue samples and analyzed changes in the translatome using the anota2seq algorithm. The analysis revealed bolstered translation of mRNAs whose translational efficiency was previously reported to be sensitive to eIF4E, a key factor for synaptic protein synthesis modulated by Ras/ERK and PI3K/mTOR signaling pathways. This observation is consistent with previous findings linking hyperactive eIF4E to increased translation of neuroligins, a disturbed excitation/inhibition ratio in synapses and autistic-like phenotypes in mice. In summary, we reveal a link between eIF4E-dependent translation and human autism, indicating a potential pharmacy-therapeutical target for the prevention of behavioral impairments in ASD.
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Project description:Perceptual anomalies in individuals with autism spectrum disorder (ASD) have been attributed to an imbalance in weighting incoming sensory evidence with prior knowledge when interpreting sensory information. Here, we show that sensory encoding and how it adapts to changing stimulus statistics during feedback also characteristically differs between neurotypical and ASD groups. In a visual orientation estimation task, we extracted the accuracy of sensory encoding from psychophysical data by using an information theoretic measure. Initially, sensory representations in both groups reflected the statistics of visual orientations in natural scenes, but encoding capacity was overall lower in the ASD group. Exposure to an artificial (i.e., uniform) distribution of visual orientations coupled with performance feedback altered the sensory representations of the neurotypical group toward the novel experimental statistics, while also increasing their total encoding capacity. In contrast, neither total encoding capacity nor its allocation significantly changed in the ASD group. Across both groups, the degree of adaptation was correlated with participants' initial encoding capacity. These findings highlight substantial deficits in sensory encoding-independent from and potentially in addition to deficits in decoding-in individuals with ASD.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-27 | GSE111176 | GEO
Project description:Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype.Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses.Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis.Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated.
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