1. Bajikar SS, Sztainberg Y, Trostle AJ, Tirumala HP, Wan YW, Harrop CL, Bengtsson JD, Carvalho CMB, Pehlivan D, Suter B, Neul JL, Liu Z, Jafar-Nejad P, Rigo F, Zoghbi HY. Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels. Hum Mol Genet. 2024; 33(22): 1986-2001.

Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.

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2. Chauhan A, Leadbitter K, Gray-Burrows KA, Vinall-Collier K, Pickles N, Baker SR, Marshman Z, Day PF. An ‘explosion in the mouth’: The oral health experiences of autistic children. Autism. 2024: 13623613241288628.

In England, one in four children have tooth decay by the age of 5 years. Tooth decay affects many autistic children. Communication differences, sensory sensitivities and preferred routines can make dental care difficult. Daily toothbrushing, healthy eating and drinking, and attending the dentist may be challenging for autistic children. We do not know much about how autistic children feel about looking after their teeth. Learning from them directly is important to understand their needs and make sure their voices are heard. We interviewed 10 autistic children aged between 7 and 13 years to discover how they care for their teeth, what helped and what did not. We talked about toothbrushing, healthy eating and drinking and visiting the dentist. To support our conversations, we used Talking Mats(®) – a tool that can help with communication. Autistic children described a wide range of sensory issues related to looking after their teeth. This finding shows how important it is to tailor care to each child’s needs. Children wanted to be included in conversations about their teeth at home and at the dentist. This was felt to make a big difference in building trust and making them feel comfortable and supported. Overall, we found Talking Mats(®) can be used in dental research to engage with autistic children. By understanding children’s views, we can better help professionals and parents to support their dental needs. Our research showed that every child’s experience is unique, so dental support must be tailored and inclusive to meet children’s needs.

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3. Chen Y, Li W, Lv L, Yue W. Shared Genetic Determinants of Schizophrenia and Autism Spectrum Disorder Implicate Opposite Risk Patterns: A Genome-Wide Analysis of Common Variants. Schizophr Bull. 2024; 50(6): 1382-95.

BACKGROUND AND HYPOTHESIS: The synaptic pruning hypothesis posits that schizophrenia (SCZ) and autism spectrum disorder (ASD) may represent opposite ends of neurodevelopmental disorders: individuals with ASD exhibit an overabundance of synapses and connections while SCZ was characterized by excessive pruning of synapses and a reduction. Given the strong genetic predisposition of both disorders, we propose a shared genetic component, with certain loci having differential regulatory impacts. STUDY DESIGN: Genome-Wide single nucleotide polymorphism (SNP) data of European descent from SCZ (N cases = 53 386, N controls = 77 258) and ASD (N cases = 18 381, N controls = 27 969) were analyzed. We used genetic correlation, bivariate causal mixture model, conditional false discovery rate method, colocalization, Transcriptome-Wide Association Study (TWAS), and Phenome-Wide Association Study (PheWAS) to investigate the genetic overlap and gene expression pattern. STUDY RESULTS: We found a positive genetic correlation between SCZ and ASD (rg = .26, SE = 0.01, P = 7.87e-14), with 11 genomic loci jointly influencing both conditions (conjFDR <0.05). Functional analysis highlights a significant enrichment of shared genes during early to mid-fetal developmental stages. A notable genetic region on chromosome 17q21.31 (lead SNP rs2696609) showed strong evidence of colocalization (PP.H4.abf = 0.85). This SNP rs2696609 is linked to many imaging-derived brain phenotypes. TWAS indicated opposing gene expression patterns (primarily pseudogenes and long noncoding RNAs [lncRNAs]) for ASD and SCZ in the 17q21.31 region and some genes (LRRC37A4P, LINC02210, and DND1P1) exhibit considerable variation in the cerebellum across the lifespan. CONCLUSIONS: Our findings support a shared genetic basis for SCZ and ASD. A common genetic variant, rs2696609, located in the Chr17q21.31 locus, may exert differential risk regulation on SCZ and ASD by altering brain structure. Future studies should focus on the role of pseudogenes, lncRNAs, and cerebellum in synaptic pruning and neurodevelopmental disorders.

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4. Ding W, Xu Y, Ding W, Tang Q, Zhang B, Yuan Y, Jin J. Research progress on melatonin, 5-HT, and orexin in sleep disorders of children with autism spectrum disorder. Biomol Biomed. 2024.

Sleep disorders are among the common comorbidities of autism spectrum disorder (ASD), which not only affect the daily life and learning ability of children but may also exacerbate other symptoms of ASD, seriously impacting the quality of life of children and their families. Given this, understanding the neurobiological mechanisms of sleep disorders in children with ASD has significant research value for developing effective intervention strategies. Melatonin, 5-HT, and orexin are key neurotransmitters that regulate the sleep-wake cycle. Through in-depth analysis of the biological functions and regulatory pathways of these neurotransmitters, new perspectives may be provided for personalized treatment of sleep disorders in children with ASD. This article reviews the research progress on melatonin, 5-HT, and orexin in sleep disorders among children with autism spectrum disorder, focusing on exploring the mechanisms of these key neurotransmitters in sleep disorders of children with ASD and how they affect the sleep-wake cycle, providing a theoretical basis for improving the sleep quality of children with ASD.

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5. Gao T, Dang W, Jiang Z, Jiang Y. Identifying the impact of ARHGAP and MAP gene families on autism spectrum disorders. PLoS One. 2024; 19(11): e0306759.

The rising incidence of Autism Spectrum Disorder (ASD) has become a major concern, affecting children’s psychological well-being and placing a significant strain on healthcare systems. Despite its impact, the etiological mechanisms underpinning ASD remain elusive. This study leveraged dorsolateral prefrontal cortex gene data from 452 individuals of European descent, sourced from the CommonMindConsortium, and examined ASD-related gene expression data from the Gene Expression Omnibus (GEO) database (GSE18123), along with Genome-Wide Association Studies (GWAS) data from the Lundbeck Foundation Integrated Psychiatric Research and Psychiatric Genomics Consortium. Expression quantitative trait loci data were sourced from the GTExv8 database. We employed Transcriptome-Wide Association Studies (TWAS) and Weighted Gene Co-expression Network Analysis (WGCNA) to pinpoint genes within ASD-associated susceptibility gene families (ARHGAP, MAP). Four genes-ARHGAP27, MAPT, ARHGAP19, and MAP1B-were scrutinized, and their biological implications were elucidated through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein-Protein Interaction (PPI) analysis and conditional analysis within the TWAS framework helped identify pivotal genes (ARHGAP27, MAPT). A subsequent verification phase involving Mendelian Randomization (MR) evaluated the potential causal links between the identified genes and ASD. The findings revealed no causal association between ARHGAP19, MAP1B, and ASD. In contrast, significant causal relationships were established for ARHGAP27 and MAPT, suggesting that ARHGAP27 may elevate ASD risk as a susceptibility gene, whereas MAPT appears to reduce the risk as a protective gene.

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6. Griffin J. Eyes are windows to the brain: Capturing eye movements to better understand face processing in autism. Science. 2024; 386(6722): 632.

Capturing eye movements to better understand face processing in autism.

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7. Mazzarella J, Heathcock JC. A Randomized Feasibility Study of Rehabilitation Targeting Upper Extremity Function and Participation Using Hippotherapy and the Equine Environment for Children with Cerebral Palsy and Autism Spectrum Disorder. J Integr Complement Med. 2024.

Introduction: Children with upper extremity neuromotor impairments often have decreased participation in life activities. Hippotherapy and rehabilitation in the equine environment might be effective in targeting participation, given the community context and natural activity involvement. This randomized controlled feasibility trial assessed recruitment, retention, treatment fidelity, and acceptability of rehabilitation using hippotherapy and the equine environment, targeting upper extremity function and participation for children with neuromotor impairments to inform a larger trial. Methods: This 6-month trial occurred in Ohio, June-December 2021. Participants were 6-17 years old with upper extremity neuromotor impairment (and primary diagnosis of cerebral palsy and/or autism). Participants were randomized into treatment or waitlist control using REDCap. Treatment was 16 h (4 h/week/4 weeks) of rehabilitation using hippotherapy and the equine environment. Control participants completed a 4-week waiting period, then received the treatment. Recruitment, screening, enrollment, attendance, and retention were tracked. Nonblinded assessments of body structures and functions, activity, and participation were administered pre- and postcontrol and treatment. Assessment measure completion, treatment fidelity, and acceptability were recorded. Results: Twenty-six participants were screened between July and October 2021; 77% (20/26) met inclusion criteria; 70% (14/20) enrolled and randomized: 6 control and 8 treatment. Two withdrew after randomization and one was excluded for fear of horses. In total, n = 5 control and n = 6 treatment completed initial assessment. Retention was 80% (4/5) control and 83% (5/6) treatment, just below the a priori criteria (85%). Assessment measure completion was variable (77%-100%) and replacement of some should be considered before advancing to a clinical trial. Treatment fidelity and acceptability were moderate to high. There were no adverse events from study participation. Conclusions: Results demonstrated preliminary evidence of fidelity and acceptability of rehabilitation using hippotherapy and the equine environment for children with upper extremity neuromotor impairments. Some changes should be made to improve enrollment, retention, and outcome measure completion before advancing to a definitive trial. Trial registration: ClinicalTrials.gov identifier: NCT0653068. Trial funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Foundation for Physical Therapy Research, American Academy of Cerebral Palsy and Developmental Medicine, and Pedal With Pete Foundation.

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8. Mitchell LK, Heussler HS, Burgess CJ, Rehman A, Steinert RE, Davies PSW. Correction: Gastrointestinal, Behaviour and Anxiety Outcomes in Autistic Children Following an Open Label, Randomised Pilot Study of Synbiotics vs Synbiotics and Gut-Directed Hypnotherapy. J Autism Dev Disord. 2024.

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9. Northrup JB, Hartman AG, MacKenzie KT, Sivathasan S, Eldeeb S, Mazefsky CA. Emotion dysregulation in autism: Severity and correlates in early childhood. Autism Res. 2024.

Emotion dysregulation (ED) is common and severe in older autistic youth, but is rarely the focus of early autism screening or intervention. Moreover, research characterizing ED in the preschool years (when autism is typically diagnosed) is limited. This study aimed to characterize ED in autistic children by examining (1) prevalence and severity of ED as compared to children without an autism diagnosis; and (2) correlates of ED in autistic children. A sample of 1864 parents (Mean child age = 4.21 years, SD = 1.16 years; 37% female) of 2-5 year-old children with (1) autism; (2) developmental concerns, but no autism; and (3) no developmental concerns or autism completed measures via an online questionnaire. ED was measured using the Emotion Dysregulation Inventory-Young Child, a parent report measure characterizing ED across two dimensions: Reactivity (fast, intense emotional reactions) and dysphoria (low positive affect, sadness, unease). Autistic preschoolers, compared to peers without developmental concerns, had more severe ED (+1.12 SD for reactivity; +0.60 SD for dysphoria) and were nearly four and three times more likely to have clinically significant reactivity and dysphoria, respectively. Autistic traits, sleep problems, speaking ability, and parent depression were the strongest correlates of ED in the autism sample. While more work is needed to establish the prevalence, severity, and correlates of ED in young autistic children, this study represents an important first step. Results highlight a critical need for more high-quality research in this area as well as the potential value of screening and intervention for ED in young autistic children.

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10. Quon AC, McClellan L, Ailey SH. Disability Education for Health Personnel and Impact on Health Outcomes for Persons with Autism: A Scoping Review. Teach Learn Med. 2024: 1-15.

Autism manifests in various progressive, fluctuating, or static differences that may be disabling. This requires healthcare staff to provide individualized, culturally competent care for autistic people (AP). However, staff are underprepared since disability curricula are not universally implemented, which may exacerbate health disparities for AP. The Alliance for Disability in Health Care Education (ADHCE) delineated staff competencies to address disparities. The purpose of this review was to describe what is known about disability education initiatives and health-related outcomes for AP. The review included published literature on disability education for any health personnel providing services to AP in any setting where healthcare services are delivered. In June 2023, six databases were queried. Of 3,396 screened reports, 42 were extracted. Most articles originated in the United States and reported various instructional strategies on child-focused educational content for small interprofessional groups in various settings. The biomedical and biopsychosocial disability models were prominent. The training covered few, if any, ADHCE competencies and rarely involved collaboration with AP. Positive outcomes included improved functional health, behavior, and communication. Patient-reported outcomes and physical and psychosocial health were underreported. Future initiatives should involve scaled-up global efforts, address core competencies for care across the lifespan, and establish community partnerships to ensure meaningful outcomes.

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11. Salerno C, Campus G, Bontà G, Vilbi G, Conti G, Cagetti MG. Oral health-related quality of life in children and adolescent with autism spectrum disorders and neurotypical peers: a nested case-control questionnaire survey. Eur Arch Paediatr Dent. 2024.

PURPOSE: Oral health-related quality of life (OHRQoL) of children with autism following an oral preventive regimen (ASDsP) was compared to that of children with autism without a preventive regimen (ASDsNP) and of neurotypical peers (NT). METHODS: An online survey was carried out using the Parental/Caregiver Perception Questionnaire (P-CPQ) and the Family Impact Scale (FIS). Scores were assigned to items, with the total score ranging from 0 to 120 (worst QoL). The median scores were compared amongst groups using the Mann-Whitney and Kruskal-Wallis tests. A multivariate linear regression assessed the relationship between questionnaire scores and demographical variables. RESULTS: Overall, 168 questionnaires from the ASDsP and the ASDsNP groups, respectively, and 336 from the NT group were selected ASDsP compared to ASDsNP showed lower P-CPQ Emotional wellbeing, FIS Emotion (p < 0.01) and Conflict (p < 0.05), and FIS total score (p < 0.01). In addition, they were less nervous (p < 0.05), shy (p < 0.01), with better sleep (p < 0.05), and with happier parents (p < 0.01). Compared to NT, ASDsP showed higher P-CPQ + FIS, P-CPQ, and FIS total scores (p < 0.01) and P-CPQ Functional limitation, Social wellbeing (p < 0.01), Emotional wellbeing (p < 0.05), and FIS Activity, Emotion and Conflict (p < 0.01). CONCLUSION: The preventive regimen reduces parental stress, improving the quality of life of children and families.

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12. Wu Q, Morrow EM, Uzun EDG. A deep learning model for prediction of autism status using whole-exome sequencing data. PLoS Comput Biol. 2024; 20(11): e1012468.

Autism is a developmental disability. Research demonstrated that children with autism benefit from early diagnosis and early intervention. Genetic factors are considered major contributors to the development of autism. Machine learning (ML), including deep learning (DL), has been evaluated in phenotype prediction, but this method has been limited in its application to autism. We developed a DL model, the Separate Translated Autism Research Neural Network (STAR-NN) model to predict autism status. The model was trained and tested using whole exome sequencing data from 43,203 individuals (16,809 individuals with autism and 26,394 non-autistic controls). Polygenic scores from common variants and the aggregated count of rare variants on genes were used as input. In STAR-NN, protein truncating variants, possibly damaging missense variants and mild effect missense variants on the same gene were separated at the input level and merged to one gene node. In this way, rare variants with different level of pathogenic effects were treated separately. We further validated the performance of STAR-NN using an independent dataset, including 13,827 individuals with autism and 14,052 non-autistic controls. STAR-NN achieved a modest ROC-AUC of 0.7319 on the testing dataset and 0.7302 on the independent dataset. STAR-NN outperformed other traditional ML models. Gene Ontology analysis on the selected gene features showed an enrichment for potentially informative pathways including potassium ion transport.

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13. Xiao Y, Zhang N, Huang K, Zhang S, Xin J, Huang Q, Yi A. Neuroanatomical basis of language ability in an autism subgroup with moderate language deficits. Eur Child Adolesc Psychiatry. 2024.

Children with autism spectrum disorder (ASD) are highly heterogenous in their language abilities. A number of studies have shown neural correlates of language deficits in children with ASD, but the underlying neuroanatomical foundation of early language deficits in ASD remains largely elusive. In this study, we analyzed MRI data from a cohort of Chinese children with ASD (n = 67) and typical development (TD, n = 37) aged 1.5 to 6.5 years. The ASD sample was classified into two subgroups based on the median of the language scores: ASD with moderate language deficits (ASD(moderate), n = 34) and ASD with severe language deficits (ASD(severe), n = 34). We tested the group differences in the brain volumes between TD and two ASD subgroups, and also examined the associations between cortical grey matter volume and language abilities in TD and ASD subgroups, separately. We observed significant group differences in grey matter and white matter volume, with post-hoc analyses specifically indicating significant differences between TD and ASD(moderate) subgroup. Significant correlations between grey matter volume and language scores were observed exclusively within the ASD(moderate) subgroup, including positive associations in the bilateral superior temporal gyrus, hippocampus, and left inferior parietal lobe, and negative correlations in the bilateral precuneus. These findings provide novel evidence for the neuroanatomical basis related to language ability in an ASD subgroup with moderate language deficits, and offer new insights into the heterogeneity of language deficits in children with ASD.

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14. Zand MS, Spallina S, Ross A, Zandi K, Pawlowski A, Seplaki CL, Herington J, Corbett AM, Kaukeinen K, Holden-Wiltse J, Freedman EG, Alcantara L, Li D, Cameron A, Beaumont N, Dozier A, Dewhurst S, Foxe JJ. Correction: Ventilation during COVID-19 in a school for students with intellectual and developmental disabilities (IDD). PLoS One. 2024; 19(11): e0313792.

[This corrects the article DOI: 10.1371/journal.pone.0291840.].

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