1. Bahado-Singh RO, Vishweswaraiah S, Aydas B, Radhakrishna U. Placental DNA methylation changes and the early prediction of autism in full-term newborns. PloS one. 2021; 16(7): e0253340.

Autism spectrum disorder (ASD) is associated with abnormal brain development during fetal life. Overall, increasing evidence indicates an important role of epigenetic dysfunction in ASD. The placenta is critical to and produces neurotransmitters that regulate fetal brain development. We hypothesized that placental DNA methylation changes are a feature of the fetal development of the autistic brain and importantly could help to elucidate the early pathogenesis and prediction of these disorders. Genome-wide methylation using placental tissue from the full-term autistic disorder subtype was performed using the Illumina 450K array. The study consisted of 14 cases and 10 control subjects. Significantly epigenetically altered CpG loci (FDR p-value <0.05) in autism were identified. Ingenuity Pathway Analysis (IPA) was further used to identify molecular pathways that were over-represented (epigenetically dysregulated) in autism. Six Artificial Intelligence (AI) algorithms including Deep Learning (DL) to determine the predictive accuracy of CpG markers for autism detection. We identified 9655 CpGs differentially methylated in autism. Among them, 2802 CpGs were inter- or non-genic and 6853 intragenic. The latter involved 4129 genes. AI analysis of differentially methylated loci appeared highly accurate for autism detection. DL yielded an AUC (95% CI) of 1.00 (1.00-1.00) for autism detection using intra- or intergenic markers by themselves or combined. The biological functional enrichment showed, four significant functions that were affected in autism: quantity of synapse, microtubule dynamics, neuritogenesis, and abnormal morphology of neurons. In this preliminary study, significant placental DNA methylation changes. AI had high accuracy for the prediction of subsequent autism development in newborns. Finally, biologically functional relevant gene pathways were identified that may play a significant role in early fetal neurodevelopmental influences on later cognition and social behavior.

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2. Fang F, Ge M, Liu J, Zhang Z, Yu H, Zhu S, Xu L, Shao L. Association between Genetic Variants in DUSP15, CNTNAP2, and PCDHA Genes and Risk of Childhood Autism Spectrum Disorder. Behavioural neurology. 2021; 2021: 4150926.

OBJECTIVE: Genetic factors play an important role in the development of autism spectrum disorder (ASD). This case-control study was to determine the association between childhood ASD and single nucleotide polymorphisms (SNPs) rs3746599 in the DUSP15 gene, rs7794745 in the CNTNAP2 gene, and rs251379 in the PCDHA gene in a Chinese Han population. METHODS: Genotypes of SNPs were examined in DNA extracted from blood cells from 201 children with ASD and 200 healthy controls. The Children Autism Rating Scale (CARS) was applied to evaluate the severity of the disease and language impairment. The relationship between SNPs and the risk of ASD or the severity of the disease was determined by logistic regression and one-way ANOVA. RESULTS: The genotype G/G of rs3746599 in the DUSP15 gene was significantly associated with a decreased risk of ASD (odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.42-0.99, P = 0.0449). The T allele of rs7794745 in the CNTNAP2 gene was associated with an increased risk of ASD (OR = 1.34, 95% CI: 1.01-1.77, P = 0.0435). The SNP rs251379 was not associated with ASD. Though none of the SNPs examined were associated with ASD severity, rs7794745 was associated with severity of language impairment. CONCLUSIONS: Our findings suggest that both rs3746599 in the DUSP15 gene and rs7794745 in the CNTNAP2 gene are associated with risk of childhood ASD, and rs7794745 is also related to the severity of language impairment in autistic children from a Chinese Han population.

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3. Frye RE, Cakir J, Rose S, Palmer RF, Austin C, Curtin P. Physiological mediators of prenatal environmental influences in autism spectrum disorder. BioEssays : news and reviews in molecular, cellular and developmental biology. 2021; 43(9): e2000307.

Recent research has pointed to the importance of the prenatal environment in the etiology of autism spectrum disorder (ASD) but the biological mechanisms which mitigate these environmental factors are not clear. Mitochondrial metabolism abnormalities, inflammation and oxidative stress as common physiological disturbances associated with ASD. Network analysis of the scientific literature identified several leading prenatal environmental factors associated with ASD, particularly air pollution, pesticides, the microbiome and epigenetics. These leading prenatal environmental factors were found to be most associated with inflammation, followed by oxidative stress and mitochondrial dysfunction. Other prenatal factors associated with ASD not identified by the network analysis were also found to be significantly associated with these common physiological disturbances. A better understanding of the biological mechanism which mediate the effect of prenatal environmental factors can lead to insights of how ASD develops and the development of targeted therapeutics to prevent ASD from occuring.

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4. Holt A, Bounekhla K, Welch C, Polatajko H. « Unheard minds, again and again »: autistic insider perspectives and theory of mind. Disability and rehabilitation. 2021: 1-11.

PURPOSE: The Theory of Mind (ToM) deficit hypothesis is a dominant construct used to explain the social and communication difficulties observed in autistic individuals. This hypothesis was based on an interpretation of autistic individuals’ observable behavior, not based on insider accounts. Insider perspectives still remain mostly absent in research on ToM. We aimed to gain an understanding of the relevance and applicability of ToM by examining writings of autistic bloggers. METHODS: As part of a series of studies examining insider autistic perspectives, we used a descriptive qualitative approach and conducted a thematic analysis of content scraped from 40 blogs written by autistic authors. RESULTS: The blogs offered important perspectives on the applicability of ToM to autistic individuals. The primary themes reflected empirical contradictions to ToM, explicit critiques of ToM, and pointed to ToM as a source of harm. CONCLUSION: The insider perspectives call into question the ways clinicians, researchers, and society use ToM to understand autistic individuals and point to the harmful effects of ToM on autistic lived experience. These findings emphasize the importance of attending to autistic people in building a body of knowledge that better reflects autistic experiences and promotes more effective and ethical clinical practices.Implications for RehabilitationOur paper indicates the need for a timely and thorough re-evaluation of the ToM deficit hypothesis of autism.Autistic insider perspectives not only empirically demonstrate and explicitly critique the ToM deficit hypothesis, but reveal the hypothesis as harmful to autistic experience by reinforcing negative stereotypes, prompting acts of discrimination, and perpetuating autistic insider’s exclusion from the research concerning them.Given the varied experiences of autistic people and the harmful impacts of the ToM deficit hypothesis, it is safer for clinicians and researchers to presume a presence of ToM and empathy, before they presume a deficit in autistic individuals.Autistic insiders are able, eager, and deserve to be included in the research and practices that concern them.

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5. Li C, Ning M, Fang P, Xu H. Sex differences in structural brain asymmetry of children with autism spectrum disorders. Journal of integrative neuroscience. 2021; 20(2): 331-40.

Previous studies have confirmed the sex difference of gray matter asymmetry in typically developing controls and the abnormal gray matter asymmetry in autism spectrum disorders. However, whether and how sex differences of gray matter asymmetry exist in autism spectrum disorders remains studied. This paper analyzes the above issues and explores correlations between gray matter asymmetry and autistic symptoms. Data from 72 children (36 males and 36 females) with autism spectrum disorders and 72 typically developing-controls (36 males and 36 females) between 8 and 14 years were included and obtained from the autism brain imaging data exchange repository (autism brain imaging data exchange I and autism brain imaging data exchange II). The voxel-based morphometry approach was used to assess gray matter asymmetry in T1-weighted brain data, and gray matter asymmetry was quantified as asymmetry index. A 2 × 2 analysis of covariance was used to identify asymmetry index differences among the four groups. Pearson correlation analysis was performed for asymmetry index values extracted from the clusters with significant differences between the four groups and autistic symptoms (social impairments, communication difficulties, and restricted, repetitive behaviors) measured by the revised autism diagnostic interview scale. Results showed that specific brain regions showed significant main effects for diagnosis in which autism spectrum disorders patients had more leftward asymmetry than typically developing-controls for the parahippocampal gyrus and the postcentral gyrus; specific brain regions showed significant main effects for sex in which females showed more rightward asymmetry for the middle temporal gyrus, inferior frontal gyrus, angular gyrus, and postcentral gyrus and minor rightward asymmetry for the superior frontal gyrus than males; significant diagnosis × sex interaction effects were identified in the angular gyrus and middle occipital gyrus. Pearson correlation analysis showed that males with autism spectrum disorders had a positive association between the asymmetry index value in the middle occipital gyrus and more significant verbal impairment measured by the revised autism diagnostic interview (r = 0.387, p = 0.026). The asymmetry index value in the parahippocampal gyrus was positively associated with more severe social impairment in females with autism spectrum disorders (r = 0.422, p = 0.020). We identified that the sex difference of gray matter asymmetry in children with autism spectrum disorders is qualitative rather than quantitative, which is relatively novel. Our findings provide the theoretical basis for conducting separate studies and using sex-specific diagnostic methods and treatments for males and females children with autism spectrum disorders.

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6. Matiello FB, Hilário JSM, Gondim EC, Santos DN, Mello DF. Health surveillance and development of children with congenital Zika Virus syndrome: an integrative literature review. Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo. 2021; 40: e2020335.

OBJECTIVE: To identify scientific knowledge about the attention to health surveillance and development of Brazilian children under the age of three years involving the Congenital Zika virus (ZIKV) Syndrome. DATA SOURCES: This is an integrative literature review of primary studies with Brazilian children under three years of age from 2015 to 2019. The searches were carried out in the databases Latin American and Caribbean Literature in Health Sciences (LILACS), US National Library of Medicine (PubMed), Cumulative Index to Nursing and Allied Health Literature (CINAHL), SCOPUS and Web of Science. It was carried out by crossing the keywords in English (child, child development and Zika virus) and in Portuguese (criança, desenvolvimento infantil e Zika vírus), with the combination of the Boolean operator « AND ». DATA SYNTHESIS: The knowledge produced is related to the specific health and development problems of children affected by the Congenital ZIKV Syndrome, with clinical characteristics, care demands, multiprofessional performance, health monitoring and surveillance needs. CONCLUSIONS: This integrative review synthesized scientific knowledge by adding aspects that reinforce the relevance of appropriate approaches to assess and care for children, linked to the engagement of caregivers, the need to document, evaluate and track the situations of children in early childhood and long-term, management coordination of care and its challenges in the context of primary health care. Publisher: Abstract available from the publisher. por.

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7. Modafferi S, Zhong X, Kleensang A, Murata Y, Fagiani F, Pamies D, Hogberg HT, Calabrese V, Lachman H, Hartung T, Smirnova L. Gene-Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres. Environmental health perspectives. 2021; 129(7): 77001.

BACKGROUND: Autism spectrum disorder (ASD) is a major public health concern caused by complex genetic and environmental components. Mechanisms of gene-environment (G × E) interactions and reliable biomarkers associated with ASD are mostly unknown or controversial. Induced pluripotent stem cells (iPSCs) from patients or with clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9)-introduced mutations in candidate ASD genes provide an opportunity to study (G × E) interactions. OBJECTIVES: In this study, we aimed to identify a potential synergy between mutation in the high-risk autism gene encoding chromodomain helicase DNA binding protein 8 (CHD8) and environmental exposure to an organophosphate pesticide (chlorpyrifos; CPF) in an iPSC-derived human three-dimensional (3D) brain model. METHODS: This study employed human iPSC-derived 3D brain organoids (BrainSpheres) carrying a heterozygote CRISPR/Cas9-introduced inactivating mutation in CHD8 and exposed to CPF or its oxon-metabolite (CPO). Neural differentiation, viability, oxidative stress, and neurite outgrowth were assessed, and levels of main neurotransmitters and selected metabolites were validated against human data on ASD metabolic derangements. RESULTS: Expression of CHD8 protein was significantly lower in CHD8 heterozygous knockout (CHD8+/-) BrainSpheres compared with CHD8+/+ ones. Exposure to CPF/CPO treatment further reduced CHD8 protein levels, showing the potential (G × E) interaction synergy. A novel approach for validation of the model was chosen: from the literature, we identified a panel of metabolic biomarkers in patients and assessed them by targeted metabolomics in vitro. A synergistic effect was observed on the cholinergic system, S-adenosylmethionine, S-adenosylhomocysteine, lactic acid, tryptophan, kynurenic acid, and α-hydroxyglutaric acid levels. Neurite outgrowth was perturbed by CPF/CPO exposure. Heterozygous knockout of CHD8 in BrainSpheres led to an imbalance of excitatory/inhibitory neurotransmitters and lower levels of dopamine. DISCUSSION: This study pioneered (G × E) interaction in iPSC-derived organoids. The experimental strategy enables biomonitoring and environmental risk assessment for ASD. Our findings reflected some metabolic perturbations and disruption of neurotransmitter systems involved in ASD. The increased susceptibility of CHD8+/- BrainSpheres to chemical insult establishes a possibly broader role of (G × E) interaction in ASD. https://doi.org/10.1289/EHP8580.

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8. Padhi EM, Hayeck TJ, Cheng Z, Chatterjee S, Mannion BJ, Byrska-Bishop M, Willems M, Pinson L, Redon S, Benech C, Uguen K, Audebert-Bellanger S, Le Marechal C, Férec C, Efthymiou S, Rahman F, Maqbool S, Maroofian R, Houlden H, Musunuri R, Narzisi G, Abhyankar A, Hunter RD, Akiyama J, Fries LE, Ng JK, Mehinovic E, Stong N, Allen AS, Dickel DE, Bernier RA, Gorkin DU, Pennacchio LA, Zody MC, Turner TN. Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism. Human genomics. 2021; 15(1): 44.

BACKGROUND: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. RESULTS: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10(-3)), and combined dataset (p = 1.1 × 10(-4)). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10(-35), loss-of-function p = 2.26 × 10(-13)) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10(-6), OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. CONCLUSIONS: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs.

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9. Peterson M, Prigge MBD, Bigler ED, Zielinski B, King JB, Lange N, Alexander A, Lainhart JE, Nielsen JA. Evidence for normal extra-axial cerebrospinal fluid volume in autistic males from middle childhood to adulthood. NeuroImage. 2021; 240: 118387.

Autism spectrum disorder has long been associated with a variety of organizational and developmental abnormalities in the brain. An increase in extra-axial cerebrospinal fluid volume in autistic individuals between the ages of 6 months and 4 years has been reported in recent studies. Increased extra-axial cerebrospinal fluid volume was predictive of the diagnosis and severity of the autistic symptoms in all of them, irrespective of genetic risk for developing the disorder. In the present study, we explored the trajectory of extra-axial cerebrospinal fluid volume from childhood to adulthood in both autism and typical development. We hypothesized that an elevated extra-axial cerebrospinal fluid volume would be found in autism persisting throughout the age range studied. We tested the hypothesis by employing an accelerated, multi-cohort longitudinal data set of 189 individuals (97 autistic, 92 typically developing). Each individual had been scanned between 1 and 5 times, with scanning sessions separated by 2-3 years, for a total of 439 T1-weighted MRI scans. A linear mixed-effects model was used to compare developmental, age-related changes in extra-axial cerebrospinal fluid volume between groups. Inconsistent with our hypothesis, we found no group differences in extra-axial cerebrospinal fluid volume in this cohort of individuals 3 to 42 years of age. Our results suggest that extra-axial cerebrospinal fluid volume in autistic individuals is not increased compared with controls beyond four years of age.

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10. Qiu J, Kong X, Li J, Yang J, Huang Y, Huang M, Sun B, Su J, Chen H, Wan G, Kong J. Transcranial Direct Current Stimulation (tDCS) over the Left Dorsal Lateral Prefrontal Cortex in Children with Autism Spectrum Disorder (ASD). Neural plasticity. 2021; 2021: 6627507.

Recently, transcranial direct current stimulation (tDCS) has been applied to relieve symptoms in individuals with autism spectrum disorder (ASD). In this prospective, parallel, single-blinded, randomized study, we investigate the modulation effect of three-week tDCS treatment at the left dorsal lateral prefrontal cortex (DLPFC) in children with ASD. 47 children with ASD were enrolled, and 40 (20 in each group) completed the study. The primary outcomes are Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), and the Repetitive Behavior Scale-Revised (RBS-R). We found that children with ASD can tolerate three-week tDCS treatment with no serious adverse events detected. A within-group comparison showed that real tDCS, but not sham tDCS, can significantly reduce the scores of CARS, Children’s Sleep Habits Questionnaire (CSHQ), and general impressions in CARS (15th item). Real tDCS produced significant score reduction in the CSHQ and in CARS general impressions when compared to the effects of sham tDCS. The pilot study suggests that three-week left DLPFC tDCS is well-tolerated and may hold potential in relieving some symptoms in children with ASD.

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11. Walter C, Marada A, Suhm T, Ernsberger R, Muders V, Kücükköse C, Sánchez-Martín P, Hu Z, Aich A, Loroch S, Solari FA, Poveda-Huertes D, Schwierzok A, Pommerening H, Matic S, Brix J, Sickmann A, Kraft C, Dengjel J, Dennerlein S, Brummer T, Vögtle FN, Meisinger C. Global kinome profiling reveals DYRK1A as critical activator of the human mitochondrial import machinery. Nature communications. 2021; 12(1): 4284.

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70(Ser91) by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70(Ser91) phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.

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