1. Aylward BS, Gal-Szabo DE, Taraman S. Racial, Ethnic, and Sociodemographic Disparities in Diagnosis of Children with Autism Spectrum Disorder. Journal of developmental and behavioral pediatrics : JDBP. 2021; 42(8): 682-9.

This special article uses a biosocial-ecological framework to discuss findings in the literature on racial, ethnic, and sociodemographic diagnostic disparities in autism spectrum disorder. We draw explanations from this framework on the complex and cumulative influences of social injustices across interpersonal and systemic levels.

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2. Das J, Hartman L, King G, Jones-Stokreef N, Moore Hepburn C, Penner M. Perspectives of Canadian Rural Consultant Pediatricians on Diagnosing Autism Spectrum Disorder: A Qualitative Study. Journal of developmental and behavioral pediatrics : JDBP. 2021; 43(3): 149-58.

BACKGROUND: Consultant pediatricians represent a potential resource for increasing autism spectrum disorder (ASD) diagnostic capacity; however, little is known about how they perceive their roles in ASD diagnosis. OBJECTIVE: The objective of this study was to examine the perspectives of rural consultant pediatricians regarding their perceived roles, facilitators, and barriers in ASD diagnosis. METHODS: We performed a qualitative study using thematic analysis. Consultant pediatricians from 3 small-sized and medium-sized Ontario communities were recruited. Semistructured interviews were conducted, transcribed, coded, and analyzed. RESULTS: Fourteen pediatricians participated in this study. Participants all considered ASD diagnosis to be in their scope of practice. The major theme identified was the process of diagnosing ASD, which occurred in 3 stages: preassessment (gathering information before the first clinic visit), diagnosis, and service access. All these stages are influenced by ecological factors consisting of characteristics of the child, family, individual physician, pediatric group practice, and the broader system of ASD care. CONCLUSION: Consultant pediatricians practicing in nonurban Ontario communities see ASD diagnosis as part of their scope of practice and collaboratively work within groups to address the needs of their communities. Strategies aimed at increasing diagnostic capacity should target salaried group practices and improve the efficiency of assessments through preclinic information gathering.

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3. Dursun A, Yalnizoglu D, Yilmaz DY, Oguz KK, Gülbakan B, Koşukcu C, Akar HT, Kahraman AB, Acar NV, Günbey C, Yildiz Y, Ozgul RK. Biallelic mutations in ELFN1 gene associated with developmental and epileptic encephalopathy and joint laxity. European journal of medical genetics. 2021; 64(11): 104340.

ELFN1, a transmembrane leucine rich repeat protein, is involved in signal transduction in both neural cells and ROD ON-bipolar synaptogenesis. We present three siblings with developmental and epileptic encephalopathy and co-morbidities due to ELFN1 gene mutation; this is the first report in literature defining the human phenotype of ELFN1 gene mutation. Clinical, electrophysiological, and radiological findings along with comprehensive genetic studies of the patients and their family members are presented. Developmental and epileptic encephalopathy, autistic features, pyramidal signs, joint laxity, and dysmorphic features are the characteristic findings of this new clinical entity, involving mainly nervous system and possibly connective tissue. Whole exome sequence analysis followed by Sanger sequencing in all family members revealed disease-causing 8 bp frameshift mutation depicted as NM_001128636.2: c.42_49delGGCCGCCA; p. (Ala15Profs*241) in ELFN1. The variant, located in the signal peptide domain in the ELFN1 gene, was found to be homozygous in three patients, and heterozygous in the parents and three healthy siblings. Segregation analysis in family members together with pathogenicity assessment tools strongly supported the damaging effect of the frameshift variant on the function of the ELFN1 protein. Mutations in ELFN1 gene may be considered in patients with neonatal and infantile-onset epileptic encephalopathy before the full clinical picture is apparent.

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4. Gao Y, Aljazi MB, Wu Y, He J. Vorinostat, a histone deacetylase inhibitor, ameliorates the sociability and cognitive memory in an Ash1L-deletion-induced ASD/ID mouse model. Neuroscience letters. 2021; 764: 136241.

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various gene mutations. Previous genetic and clinical studies reported that ASH1L is a high ASD risk gene identified in human patients. Our recent study used a mouse model to demonstrate that loss of ASH1L in the developing mouse brain was sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory, suggesting that the disruptive ASH1L mutations are the causative drivers leading the human ASD/ID genesis. Using this Ash1L-deletion-induced ASD/ID mouse model, here we showed that postnatal administration of vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), significantly ameliorated both ASD-like behaviors and ID-like cognitive memory deficit. Thus, our study demonstrates that SAHA is a promising reagent for the pharmacological treatment of core ASD/ID behavioral and memory deficits caused by disruptive ASH1L mutations.

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5. Kissoondoyal A, Rai-Bhogal R, Crawford DA. Abnormal dendritic morphology in the cerebellum of cyclooxygenase-2(-) knockin mice. The European journal of neuroscience. 2021; 54(7): 6355-73.

Prostaglandin E2 (PGE2) is a bioactive signalling molecule metabolized from the phospholipid membranes by the enzymatic activity of cycloxygenase-2 (COX-2). In the developing brain, COX-2 constitutively regulates the production of PGE2, which is important in neuronal development. However, abnormal COX-2/PGE2 signalling has been linked to neurodevelopmental disorders including autism spectrum disorders (ASDs). We have previously demonstrated that COX-2(-) -KI mice show autism-related behaviours including social deficits, repetitive behaviours and anxious behaviours. COX-2-deficient mice also have deficits in pathways involved in synaptic transmission and dendritic spine formation. In this study, we use a Golgi-COX staining method to examine sex-dependent differences in dendritic and dendritic spine morphology in neurons of COX-2(-) -KI mice cerebellum compared with wild-type (WT) matched controls at postnatal day 25 (P25). We show that COX-2(-) -KI mice have increased dendritic arborization closer to the cell soma and increased dendritic looping. We also observed a sex-dependent effect of the COX-2(-) -KI on dendritic thickness, dendritic spine density, dendritic spine morphology, and the expression of β-actin and the actin-binding protein spinophilin. Our findings show that changes in COX-2/PGE2 signalling lead to impaired morphology of dendrites and dendritic spines in a sex-dependant manner and may contribute the pathology of the cerebellum seen in individuals with ASD. This study provides further evidence that the COX-2(-) -KI mouse model can be used to study a subset of ASD pathologies.

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6. Mo K, Sadoway T, Bonato S, Ameis SH, Anagnostou E, Lerch JP, Taylor MJ, Lai MC. Sex/gender differences in the human autistic brains: A systematic review of 20 years of neuroimaging research. NeuroImage Clinical. 2021; 32: 102811.

Our current understanding of autism is largely based on clinical experiences and research involving male individuals given the male-predominance in prevalence and the under-inclusion of female individuals due to small samples, co-occurring conditions, or simply being missed for diagnosis. There is a significantly biased ‘male lens’ in this field with autistic females insufficiently understood. We therefore conducted a systematic review to examine how sex and gender modulate brain structure and function in autistic individuals. Findings from the past 20 years are yet to converge on specific brain regions/networks with consistent sex/gender-modulating effects. Despite at least three well-powered studies identifying specific patterns of significant sex/gender-modulation of autism-control differences, many other studies are likely underpowered, suggesting a critical need for future investigation into sex/gender-based heterogeneity with better-powered designs. Future research should also formally investigate the effects of gender, beyond biological sex, which is mostly absent in the current literature. Understanding the roles of sex and gender in the development of autism is an imperative step to extend beyond the ‘male lens’ in this field.

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7. Modenato C, Martin-Brevet S, Moreau CA, Rodriguez-Herreros B, Kumar K, Draganski B, Sønderby IE, Jacquemont S. Lessons Learned From Neuroimaging Studies of Copy Number Variants: A Systematic Review. Biological psychiatry. 2021; 90(9): 596-610.

Pathogenic copy number variants (CNVs) and aneuploidies alter gene dosage and are associated with neurodevelopmental psychiatric disorders such as autism spectrum disorder and schizophrenia. Brain mechanisms mediating genetic risk for neurodevelopmental psychiatric disorders remain largely unknown, but there is a rapid increase in morphometry studies of CNVs using T1-weighted structural magnetic resonance imaging. Studies have been conducted one mutation at a time, leaving the field with a complex catalog of brain alterations linked to different genomic loci. Our aim was to provide a systematic review of neuroimaging phenotypes across CNVs associated with developmental psychiatric disorders including autism and schizophrenia. We included 76 structural magnetic resonance imaging studies on 20 CNVs at the 15q11.2, 22q11.2, 1q21.1 distal, 16p11.2 distal and proximal, 7q11.23, 15q11-q13, and 22q13.33 (SHANK3) genomic loci as well as aneuploidies of chromosomes X, Y, and 21. Moderate to large effect sizes on global and regional brain morphometry are observed across all genomic loci, which is in line with levels of symptom severity reported for these variants. This is in stark contrast with the much milder neuroimaging effects observed in idiopathic psychiatric disorders. Data also suggest that CNVs have independent effects on global versus regional measures as well as on cortical surface versus thickness. Findings highlight a broad diversity of regional morphometry patterns across genomic loci. This heterogeneity of brain patterns provides insight into the weak effects reported in magnetic resonance imaging studies of cognitive dimension and psychiatric conditions. Neuroimaging studies across many more variants will be required to understand links between gene function and brain morphometry.

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8. Salemi M, Cannarella R, Marchese G, Salluzzo MG, Ravo M, Barone C, Giudice ML, Calogero AE, Romano C. Role of long non-coding RNAs in Down syndrome patients: a transcriptome analysis study. Human cell. 2021; 34(6): 1662-70.

Down syndrome (DS) is defined by the presence of a third copy of chromosome 21. Several comorbidities can be found in these patients, such as intellectual disability (ID), muscle weakness, hypotonia, congenital heart disease, and autoimmune diseases. The molecular mechanisms playing a role in the development of such comorbidities are still unclear. The regulation and expression of genes that map to chromosome 21 are dynamic and complex, so it is important to perform global gene expression studies with high statistical power to fully characterize the transcriptome in DS patients. This study was undertaken to evaluate mRNAs and lncRNA expression in patients with DS versus a matched cohort of healthy subjects. RNA sequencing was used to perform this transcriptome study. Differential expression analysis revealed 967 transcripts with padj ≤ 0.05. Among them, 447 transcripts were differentially expressed in patients with DS compared to controls. Particularly, 203 transcripts were down expressed (151 protein-coding mRNAs, 45 lncRNAs, 1 microRNA, 1 mitochondrial tRNA, 1 ribozyme, and 1 small nuclear RNA) and 244 were over expressed (210 protein-coding mRNAs and 34 lncRNAs). Interestingly, deregulated lncRNAs are involved in pathways that play a role in developmental disorders, neurological diseases, DNA replication and repair mechanisms, and cancer development in DS patients. In conclusion, these results suggest a role of lncRNAs in the phenotype of DS patients.

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