1. Abdi M, Aliyev E, Trost B, Kohailan M, Aamer W, Syed N, Shaath R, Gandhi GD, Engchuan W, Howe J, Thiruvahindrapuram B, Geng M, Whitney J, Syed A, Lakshmi J, Hussein S, Albashir N, Hussein A, Poggiolini I, Elhag SF, Palaniswamy S, Kambouris M, de Fatima Janjua M, Tahir MOE, Nazeer A, Shahwar D, Azeem MW, Mokrab Y, Aati NA, Akil A, Scherer SW, Kamal M, Fakhro KA. Genomic architecture of autism spectrum disorder in Qatar: The BARAKA-Qatar Study. Genome Med;2023 (Oct 7);15(1):81.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social and communication skills, restricted interests, and repetitive behaviors. The prevalence of ASD among children in Qatar was recently estimated to be 1.1%, though the genetic architecture underlying ASD both in Qatar and the greater Middle East has been largely unexplored. Here, we describe the first genomic data release from the BARAKA-Qatar Study-a nationwide program building a broadly consented biorepository of individuals with ASD and their families available for sample and data sharing and multi-omics research. METHODS: In this first release, we present a comprehensive analysis of whole-genome sequencing (WGS) data of the first 100 families (372 individuals), investigating the genetic architecture, including single-nucleotide variants (SNVs), copy number variants (CNVs), tandem repeat expansions (TREs), as well as mitochondrial DNA variants (mtDNA) segregating with ASD in local families. RESULTS: Overall, we identify potentially pathogenic variants in known genes or regions in 27 out of 100 families (27%), of which 11 variants (40.7%) were classified as pathogenic or likely-pathogenic based on American College of Medical Genetics (ACMG) guidelines. Dominant variants, including de novo and inherited, contributed to 15 (55.6%) of these families, consisting of SNVs/indels (66.7%), CNVs (13.3%), TREs (13.3%), and mtDNA variants (6.7%). Moreover, homozygous variants were found in 7 families (25.9%), with a sixfold increase in homozygous burden in consanguineous versus non-consanguineous families (13.6% and 1.8%, respectively). Furthermore, 28 novel ASD candidate genes were identified in 20 families, 23 of which had recurrent hits in MSSNG and SSC cohorts. CONCLUSIONS: This study illustrates the value of ASD studies in under-represented populations and the importance of WGS as a comprehensive tool for establishing a molecular diagnosis for families with ASD. Moreover, it uncovers a significant role for recessive variation in ASD architecture in consanguineous settings and provides a unique resource of Middle Eastern genomes for future research to the global ASD community.

Lien vers le texte intégral (Open Access ou abonnement)

2. Ismail E, Gad W, Hashem M. A hybrid Stacking-SMOTE model for optimizing the prediction of autistic genes. BMC Bioinformatics;2023 (Oct 6);24(1):379.

PURPOSE: Autism spectrum disorder(ASD) is a disease associated with the neurodevelopment of the brain. The autism spectrum can be observed in early childhood, where the symptoms of the disease usually appear in children within the first year of their life. Currently, ASD can only be diagnosed based on the apparent symptoms due to the lack of information on genes related to the disease. Therefore, in this paper, we need to predict the largest number of disease-causing genes for a better diagnosis. METHODS: A hybrid stacking ensemble model with Synthetic Minority Oversampling TEchnique (Stack-SMOTE) is proposed to predict the genes associated with ASD. The proposed model uses the gene ontology database to measure the similarities between the genes using a hybrid gene similarity function(HGS). HGS is effective in measuring the similarity as it combines the features of information gain-based methods and graph-based methods. The proposed model solves the imbalanced ASD dataset problem using the Synthetic Minority Oversampling Technique (SMOTE), which generates synthetic data rather than duplicates the data to reduce the overfitting. Sequentially, a gradient boosting-based random forest classifier (GBBRF) is introduced as a new combination technique to enhance the prediction of ASD genes. Moreover, the GBBRF classifier combined with random forest(RF), k-nearest neighbor, support vector machine(SVM), and logistic regression(LR) to form the proposed Stacking-SMOTE model to optimize the prediction of ASD genes. RESULTS: The proposed Stacking-SMOTE model is evaluated using the Simons Foundation Autism Research Initiative (SFARI) gene database and a set of candidates ASD genes.The results of the proposed model-based SMOTE outperform other reported undersampling and oversampling techniques. Sequentially, the results of GBBRF achieve higher accuracy than using the basic classifiers. Moreover, the experimental results show that the proposed Stacking-SMOTE model outperforms the existing ASD prediction models with approximately 95.5% accuracy. CONCLUSION: The proposed Stacking-SMOTE model demonstrates that SMOTE is effective in handling the autism imbalanced data. Sequentially, the integration between the gradient boosting and random forest classifier (GBBRF) support to build a robust stacking ensemble model(Stacking-SMOTE).

Lien vers le texte intégral (Open Access ou abonnement)

3. O’Reilly C, Huberty S, van Noordt S, Desjardins J, Wright N, Scorah J, Webb SJ, Elsabbagh M. EEG functional connectivity in infants at elevated familial likelihood for autism spectrum disorder. Mol Autism;2023 (Oct 7);14(1):37.

BACKGROUND: Many studies have reported that autism spectrum disorder (ASD) is associated with atypical structural and functional connectivity. However, we know relatively little about the development of these differences in infancy. METHODS: We used a high-density electroencephalogram (EEG) dataset pooled from two independent infant sibling cohorts, to characterize such neurodevelopmental deviations during the first years of life. EEG was recorded at 6 and 12 months of age in infants at typical (N = 92) or elevated likelihood for ASD (N = 90), determined by the presence of an older sibling with ASD. We computed the functional connectivity between cortical sources of EEG during video watching using the corrected imaginary part of phase-locking values. RESULTS: Our main analysis found no significant association between functional connectivity and ASD, showing only significant effects for age, sex, age-sex interaction, and site. Given these null results, we performed an exploratory analysis and observed, at 12 months, a negative correlation between functional connectivity and ADOS calibrated severity scores for restrictive and repetitive behaviors (RRB). LIMITATIONS: The small sample of ASD participants inherent to sibling studies limits diagnostic group comparisons. Also, results from our secondary exploratory analysis should be considered only as potential relationships to further explore, given their increased vulnerability to false positives. CONCLUSIONS: These results are inconclusive concerning an association between EEG functional connectivity and ASD in infancy. Exploratory analyses provided preliminary support for a relationship between RRB and functional connectivity specifically, but these preliminary observations need corroboration on larger samples.

Lien vers le texte intégral (Open Access ou abonnement)

4. Pruneti C, Coscioni G, Guidotti S. Evaluation of the effectiveness of behavioral interventions for autism spectrum disorders: A systematic review of randomized controlled trials and quasi-experimental studies. Clin Child Psychol Psychiatry;2023 (Oct 6):13591045231205614.

The objective of this research was to assess the efficacy of behavioral therapy interventions in the treatment of autism spectrum disorders (ASD). The study utilized the PubMed and Embase databases to locate randomized controlled trials, quasi-experimental treatment studies, and randomized clinical trial comparisons. The experimental group received treatment based on an applied behavioral approach, such as PECS, DTT, PRT, TEACCH, ESDM, and EIBI. After examining seventeen studies, the researchers found that each type of behavioral intervention had a positive impact. Naturalistic protocols that employed PRT and PECS improved ASD symptoms in general, despite their targeting of particular cognitive domains such as language. ESDM enhanced receptive language, particularly in preschool-aged children. Structured and integrated interventions, like EIBI and TEACCH, improved overall adaptive functioning. Combining DTT with a TEACCH program produced greater benefits in linguistic, affective-social, and personal autonomy domains. However, there is a scarcity of high-quality research available on behavioral interventions for ASD. Further comparative studies are necessary to identify cost-efficient interventions. For example, PRT and PECS significantly improved social communication skills in only 15-40 hours over six months. The authors emphasized the need for continued research and the application of evidence-based interventions in specialized settings.

Lien vers le texte intégral (Open Access ou abonnement)

5. Shi X, Lu C, Corman A, Nikish A, Zhou Y, Platt RJ, Iossifov I, Zhang F, Pan JQ, Sanjana NE. Heterozygous deletion of the autism-associated gene CHD8 impairs synaptic function through widespread changes in gene expression and chromatin compaction. Am J Hum Genet;2023 (Oct 5);110(10):1750-1768.

Whole-exome sequencing of autism spectrum disorder (ASD) probands and unaffected family members has identified many genes harboring de novo variants suspected to play a causal role in the disorder. Of these, chromodomain helicase DNA-binding protein 8 (CHD8) is the most recurrently mutated. Despite the prevalence of CHD8 mutations, we have little insight into how CHD8 loss affects genome organization or the functional consequences of these molecular alterations in neurons. Here, we engineered two isogenic human embryonic stem cell lines with CHD8 loss-of-function mutations and characterized differences in differentiated human cortical neurons. We identified hundreds of genes with altered expression, including many involved in neural development and excitatory synaptic transmission. Field recordings and single-cell electrophysiology revealed a 3-fold decrease in firing rates and synaptic activity in CHD8(+/-) neurons, as well as a similar firing-rate deficit in primary cortical neurons from Chd8(+/-) mice. These alterations in neuron and synapse function can be reversed by CHD8 overexpression. Moreover, CHD8(+/-) neurons displayed a large increase in open chromatin across the genome, where the greatest change in compaction was near autism susceptibility candidate 2 (AUTS2), which encodes a transcriptional regulator implicated in ASD. Genes with changes in chromatin accessibility and expression in CHD8(+/-) neurons have significant overlap with genes mutated in probands for ASD, intellectual disability, and schizophrenia but not with genes mutated in healthy controls or other disease cohorts. Overall, this study characterizes key molecular alterations in genome structure and expression in CHD8(+/-) neurons and links these changes to impaired neuronal and synaptic function.

Lien vers le texte intégral (Open Access ou abonnement)

6. You M, Li S, Yan S, Yao D, Wang T, Wang Y. Exposure to nonylphenol in early life causes behavioural deficits related with autism spectrum disorders in rats. Environ Int;2023 (Sep 27);180:108228.

Early-life exposure to environmental endocrine disruptors (EDCs) is a potential risk factor for autism spectrum disorder (ASD). Exposure to nonylphenol (NP), a typical EDC, is known to cause some long-term behavioural abnormalities. Moreover, these abnormal behaviours are the most frequent psychiatric co-morbidities in ASD. However, the direct evidence for the link between NP exposure in early life and ASD-like behavioural phenotypes is still missing. In the present study, typical ASD-like behaviours induced by valproic acid treatment were considered as a positive behavioural control. We investigated impacts on social behaviours following early-life exposure to NP, and explored effects of this exposure on neuronal dendritic spines, mitochondria function, oxidative stress, and endoplasmic reticulum (ER) stress. Furthermore, primary cultured rat neurons were employed as in vitro model to evaluate changes in dendritic spine caused by exposure to NP, and oxidative stress and ER stress were specifically modulated to further explore their roles in these changes. Our results indicated rats exposed to NP in early life showed mild ASD-like behaviours. Moreover, we also found the activation of ER stress triggered by oxidative stress may contribute to dendritic spine decrease and synaptic dysfunction, which may underlie neurobehavioural abnormalities induced by early-life exposure to NP.

Lien vers le texte intégral (Open Access ou abonnement)

7. You XR, Gong XR, Guo MR, Ma BX. Cognitive behavioural therapy to improve social skills in children and adolescents with autism spectrum disorder: A meta-analysis of randomised controlled trials. J Affect Disord;2023 (Oct 4)

BACKGROUND: Cognitive behavioural therapy (CBT) is effective in treating various neurological and psychiatric diseases. It improves anxiety symptoms in children with autism spectrum disorder, gaining considerable empirical support. However, social skills results are mixed, leading to debate over its effectiveness, highlighting the need for further development. While the Social Responsiveness Scale (SRS) is a secondary indicator to measure anxiety symptoms, it primarily evaluates social skills, which are essential for rehabilitating children with autism. Therefore, evaluating social disorder improvement in children with autism is imperative. Social impairment is a core autism symptom. Therefore, we conducted a systematic review of randomised controlled trials assessing the effects of CBT on social skills in this population. METHODS: We reviewed articles published in several databases through October 2022 and relevant reference lists. We used the standardised mean difference (SMD) as the main effect size indicator and focused on SRS metrics from baseline to endpoint. We analysed subgroups, heterogeneity, bias risk, and publication bias. RESULTS: Our meta-analysis included 214 children from seven randomised controlled trials with nine datasets. Forest plot analysis shows CBT improved social skills in children with autism compared to controls. Subgroup analysis revealed parents’ and teachers’ SRS scores for children, SRS scores of CBT versus waitlist controls, and those of CBT versus non-waiting-list controls. LIMITATIONS: Most randomised controlled CBT trials for children with autism have explored anxiety symptom improvement. Further, social skill assessment was a secondary outcome or not assessed. Thus, social skills data are insufficient. CONCLUSIONS: CBT is effective in improving social impairment in children with autism. REGISTRATION: This meta-analysis was registered with the International Prospective Register of Systematic Reviews (CRD42022363423).

Lien vers le texte intégral (Open Access ou abonnement)