Association of GTF2i in the Williams-Beuren Syndrome Critical Region with Autism Spectrum Disorders
Patrick MalenfantXudong LiuMelissa L. HudsonYing QiaoMonica HrynchakNoémie RiendeauMark HildebrandIra L. CohenAlbert E. ChudleyCynthia Forster‐GibsonElizabeth C. R. MickelsonEvica Rajcan‐SeparovicM. E. Suzanne LewisJeanette J. A. Holden
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Williams Syndrome
Heritability of autism
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Autism spectrum disorder (ASD) is gathering concerns in socially developed countries. ASD is a neuropsychiatric disorder of genetic origin with high prevalence of 1%–2%. The patients with ASD characteristically show impaired social skills. Today, many genetic studies identify numerous susceptible genes and genetic loci associated with ASD. Although some genetic factors can lead to abnormal brain function linked to ASD phenotypes, the pathogenic mechanism of ASD is still unclear. Here, we discuss a new mouse model for ASD as an advanced tool to understand the mechanism of ASD.
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Thesis by publication.%%%%%%%%%%%%General introduction – Paper 1. Extending the positive bias in Williams syndrome : the influence of biographical information on attention allocation – Paper 2. Attention for faces in Williams syndrome, Autism spectrum disorder and Social anxiety disorder : the role of biographical information – Paper 3. Emotional recognition in Williams syndrome, Autism spectrum disorder and Social anxiety disorder : the influence of biographical information – Paper 4. Visual attention and executive function in Williams syndrome, Autism spectrum disorder and Social anxiety disorder : the role of biographical information – Paper 5. Visual scanpaths and social approach judgements in Williams syndrome, Autism spectrum disorder and Social anxiety disorder : use of biographical rather than affective stimuli – General discussion – Ethics approval.%%%%Williams syndrome (WS), Autism Spectrum Disorder (ASD) and Social Anxiety Disorder (SoAD) are conditions which present with contrasting social profiles. With respect to social processing and social behaviour, these conditions appear to represent distinct points on a continuum, from increased social approach in WS, to social withdrawal and avoidance in ASD and SoAD. While social processing anomalies have been established across WS, ASD and SoAD, research to date has largely investigated each condition in isolation. Moreover, while it is known that individuals with these conditions display social processing abnormalities in response to emotional face stimuli, it is not known whether similar abnormalities are observed in response to biographical stimuli.%%%%This thesis aimed to assess the influence of biographical information on social processing in individuals with WS, ASD or SoAD, using a cross-disorder comparison. A biographical learning paradigm was adapted and implemented across five papers, specifically investigating the influence of biographical information on attention allocation, emotion recognition, the salience of certain face regions and approach/avoidance decisions.%%%%The principal findings of this thesis are as follows: 1) Biographical information influences attention allocation, with WS individuals exhibiting an attention bias for trustworthy biographical faces, while SoAD individuals display an attention bias for untrustworthy biographical faces. 2) Biographical information does not influence the direct perception of emotional expressions, however; 3) Biographical information influences the salience of the eye region of faces, with WS individuals spending more time looking at the eyes of trustworthy biographical faces, while ASD and SoAD individuals spend more time looking at the eyes of untrustworthy biographical faces. 4) Across WS, ASD and SoAD, social approach judgments are directly influenced by biographical information.%%%%Thus, using a cross-disorder comparison, this thesis showed that biographical information does influence social processing across WS, ASD and SoAD, largely in the direction that one would predict based on their…
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Autism is a severe neurodevelopmental disorder with a strong genetic basis.The methyl-CpG binding protein 2 gene (MECP2) is a dosage-sensitive gene in brain development and has been implicated as a candidate gene for autism. Duplication of the MECP2 gene has been reported in a few boys with autistic features. To further investigate the association of MECP2 duplication with autism, the authors performed real-time quantitative polymerase chain reaction (PCR) to detect copy number variations of the MECP2 gene in 82 autistic boys. No copy number variation was found in these patients, indicating that duplication of the MECP2 gene is not frequent in autistic patients. The authors consider that duplication of the MECP2 gene has no major effect on the susceptibility to autism. Replication of studies in a large-sized sample and a well-characterized subgroup of autism are warranted to further identify the association of MECP2 gene duplication with autism.
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It was recently postulated that because increased genetic load and increased parental age are both purportedly associated with the risk to develop an autism spectrum disorder, there must be a linkage between increasing genetic load and increasing parental age in autism spectrum disorder pathogenesis. The present study examined the hypothesis that if increased genetic load from increasing paternal age is important to autism spectrum disorder pathogenesis, then there should be a significant relationship between increasing parental age and increasing autism spectrum disorder phenotypic severity. Outpatient clinical records were retrospectively examined to identify a consecutive cohort of subjects diagnosed with an autism spectrum disorder (n = 351). Increasing autism spectrum disorder phenotypic severity was found not to be associated with increasing maternal/paternal age. The present study failed to support the hypothesis that increasing parental age was associated with increasing autism spectrum disorder phenotypic severity, but future studies should examine the relationship between genetic mutations in subjects diagnosed with an autism spectrum disorder and increasing parental age.
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OBJECTIVE. In addition to the core behavioral symptoms of autism spectrum disorder, many patients present with complex medical conditions including gastrointestinal dysfunction. A functional variant in the promoter of the gene encoding the MET receptor tyrosine kinase is associated with autism spectrum disorder, and MET protein expression is decreased in the temporal cortex of subjects with autism spectrum disorder. MET is a pleiotropic receptor that functions in both brain development and gastrointestinal repair. On the basis of these functions, we hypothesized that association of the autism spectrum disorder–associated MET promoter variant may be enriched in a subset of individuals with co-occurring autism spectrum disorder and gastrointestinal conditions. PATIENTS AND METHODS. Subjects were 918 individuals from 214 Autism Genetics Resource Exchange families with a complete medical history including gastrointestinal condition report. Genotypes at the autism spectrum disorder–associated MET promoter variant rs1858830 were determined. Family-based association test and χ2 analyses were used to determine the association of MET rs1858830 alleles with autism spectrum disorder and the presence of gastrointestinal conditions. RESULTS. In the entire 214-family sample, the MET rs1858830 C allele was associated with both autism spectrum disorder and gastrointestinal conditions. Stratification by the presence of gastrointestinal conditions revealed that the MET C allele was associated with both autism spectrum disorder and gastrointestinal conditions in 118 families containing at least 1 child with co-occurring autism spectrum disorder and gastrointestinal conditions. In contrast, there was no association of the MET polymorphism with autism spectrum disorder in the 96 families lacking a child with co-occurring autism spectrum disorder and gastrointestinal conditions. χ2 analyses of MET rs1858830 genotypes indicated over-representation of the C allele in individuals with co-occurring autism spectrum disorder and gastrointestinal conditions compared with non-autism spectrum disorder siblings, parents, and unrelated controls. CONCLUSION. These results suggest that disrupted MET signaling may contribute to increased risk for autism spectrum disorder that includes familial gastrointestinal dysfunction.
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According to this study: The variation in the occurrence of autism spectrum disorder in the population is mostly due to genetic influences, with little evidence of maternal effects. The heritability of autism spectrum disorder was estimated to be approximately 80%.
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Autism spectrum disorder(ASD) is gathering concerns in socially developed countries. ASD is a neuropsychiatric disorder of genetic origin with high prevalence of 1%–2%. The patients with ASD characteristically show impaired social skills. Today, many genetic studies identify numerous susceptible genes and genetic loci associated with ASD. Although some genetic factors can lead to abnormal brain function linked to ASD phenotypes, the pathogenic mechanism of ASD is still unclear. Here, we discuss a new mouse model for ASD as an advanced tool to understand the mechanism of ASD.
Heritability of autism
Spectrum disorder
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