1. Bajracharya L, Lall M, Bijarnia-Mahay S, Kumar P, Mushtaq I, Saviour P, Paliwal P, Joshi A, Agarwal S, Suman P. A Rare Case of Mosaic 3pter and 5pter Deletion-Duplication with Autism Spectrum Disorder and Dyskinesia. Case Rep Genet;2023;2023:7974886.

INTRODUCTION: There is evidence that neurodevelopmental disorders are associated with chromosomal abnormalities. Current genetic testing can clinch an exact diagnosis in 20-25% of such cases. Case Description. A 3 years and 11 months old boy with global developmental delay had repetitive behaviors and hyperkinetic movements. He was stunted and underweight. He had ataxia, limb dyskinesia, triangular face, microcephaly, upward slanting palpebral fissure, hypertelorism, retrognathia, posteriorly rotated ears, long philtrum, thin lips, broad nasal tip, polydactyly, tappering fingers, and decreased tone in the upper and lower limbs with normal deep tendon reflexes. Magnetic resonance imaging of the brain, ultrasound of the abdomen, and ophthalmological evaluation were normal. Brain evoked response auditory revealed bilateral moderate hearing loss. He fulfilled the Diagnostic Statistical Manual 5 criteria for autism. In the Vineland Social Maturity Scale, his score indicated a severe delay in social functioning. His genetic evaluation included karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA). The karyotype report from high-resolution lymphocyte cultures was mos 46, XY, der(3)t(3; 5)(p26; p15.3)[50]/46, XY,der(5) t(3;5) (p26;p15.3)[50].ish. His karyotype report showed a very rare and abnormal mosaic pattern with two cell lines (50% each). Cell-line#1: 3pter deletion with 5pter duplication (3pter-/5pter+) and cell-line#2: 3pter duplication with 5pter deletion (3pter+/5pter-) derived from a de novo reciprocal translocation t(3; 5)(p26; p15.3) which was confirmed by FISH. The chromosomal microarray analysis report was normal. The two cell lines (50% each) seem to have balanced out at the whole genome level. Occupational, sensory integration, and behavior modification therapy were initiated for his autistic features, and anticholinergic trihexiphenidyl was prescribed for hyperkinetic movements. CONCLUSION: This case highlights a rare genetic finding and the need for timely genetic testing in a child with dysmorphism and autism with movement disorder to enable appropriate management and genetic counselling.

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2. Boyd NK, Nguyen J, Khoshnood MM, Jiang T, Nguyen L, Mendez L, Spinazzi NA, Manning MA, Rafii MS, Santoro JD. Hypovitaminosis D in persons with Down syndrome and autism spectrum disorder. J Neurodev Disord;2023 (Oct 25);15(1):35.

BACKGROUND: Plasma levels of vitamin D have been reported to be low in persons with Down syndrome (DS) and existing data is limited to small and homogenous cohorts. This is of particular importance in persons with DS given the high rates of autoimmune disease in this population and the known relationship between vitamin D and immune function. This study sought to investigate vitamin D status in a multi-center cohort of individuals with DS and compare them to individuals with autism spectrum disorder (ASD) and neurotypical (NT) controls. METHODS: A retrospective, multi-center review was performed. The three sites were located at latitudes of 42.361145, 37.44466, and 34.05349. Patients were identified by the International Classification of Diseases (ICD)-9 or ICD-10 codes for DS, ASD, or well-child check visits for NT individuals. The first vitamin D 25-OH level recorded in the electronic medical record (EMR) was used in this study as it was felt to be the most reflective of a natural and non-supplemented state. Vitamin D 25-OH levels below 30 ng/mL were considered deficient. RESULTS: In total, 1624 individuals with DS, 5208 with ASD, and 30,775 NT controls were identified. Individuals with DS had the lowest mean level of vitamin D 25-OH at 20.67 ng/mL, compared to those with ASD (23.48 ng/mL) and NT controls (29.20 ng/mL) (p < 0.001, 95% CI: -8.97 to -6.44). A total of 399 (24.6%) individuals with DS were considered vitamin D deficient compared to 1472 (28.3%) with ASD and 12,397 (40.3%) NT controls (p < 0.001, 95% CI: -5.43 to -2.36). Individuals with DS with higher body mass index (BMI) were found to be more likely to have lower levels of vitamin D (p < 0.001, 95% CI: -0.3849 to -0.1509). Additionally, having both DS and a neurologic diagnosis increased the likelihood of having lower vitamin D levels (p < 0.001, 95% CI: -5.02 to -1.28). Individuals with DS and autoimmune disease were much more likely to have lower vitamin D levels (p < 0.001, 95% CI: -6.22 to -1.55). Similarly, a history of autoimmunity in a first-degree relative also increased the likelihood of having lower levels of vitamin D in persons with DS (p = 0.01, 95% CI: -2.45 to -0.63). CONCLUSIONS: Individuals with DS were noted to have hypovitaminosis D in comparison to individuals with ASD and NT controls. Associations between vitamin D deficiency and high BMI, personal autoimmunity, and familial autoimmunity were present in individuals with DS.

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3. Chamtouri M, Gaddour N, Merghni A, Mastouri M, Arboleya S, de Los Reyes-Gavilán CG. Age and severity-dependent gut microbiota alterations in Tunisian children with autism spectrum disorder. Sci Rep;2023 (Oct 25);13(1):18218.

Alterations in gut microbiota and short chain fatty acids (SCFA) have been reported in autism spectrum disorder (ASD). We analysed the gut microbiota and fecal SCFA in Tunisian autistic children from 4 to 10 years, and results were compared to those obtained from a group of siblings (SIB) and children from the general population (GP). ASD patients presented different gut microbiota profiles compared to SIB and GP, with differences in the levels of Bifidobacterium and Collinsella occurring in younger children (4-7 years) and that tend to be attenuated at older ages (8-10 years). The lower abundance of Bifidobacterium is the key feature of the microbiota composition associated with severe autism. ASD patients presented significantly higher levels of propionic and valeric acids than GP at 4-7 years, but these differences disappeared at 8-10 years. To the best of our knowledge, this is the first study on the gut microbiota profile of Tunisian autistic children using a metataxonomic approach. This exploratory study reveals more pronounced gut microbiota alterations at early than at advanced ages in ASD. Although we did not account for multiple testing, our findings suggest that early interventions might mitigate gut disorders and cognitive and neurodevelopment impairment associated to ASD.

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4. Chari T, Hernandez A, Portera-Cailliau C. A Novel Head-Fixed Assay for Social Touch in Mice Uncovers Aversive Responses in Two Autism Models. J Neurosci;2023 (Oct 25);43(43):7158-7174.

Social touch, an important aspect of social interaction and communication, is essential to kinship across animal species. How animals experience and respond to social touch has not been thoroughly investigated, in part because of the lack of appropriate assays. Previous studies that examined social touch in freely moving rodents lacked the necessary temporal and spatial control over individual touch interactions. We designed a novel head-fixed assay for social touch in mice, in which the experimenter has complete control to elicit highly stereotyped bouts of social touch between two animals. The user determines the number, duration, context, and type of social touch interactions, while monitoring an array of complex behavioral responses with high resolution cameras. We focused on social touch to the face because of its high translational relevance to humans. We validated this assay in two different models of autism spectrum disorder (ASD), the Fmr1 knock-out (KO) model of Fragile X syndrome (FXS) and maternal immune activation (MIA) mice. We observed higher rates of avoidance running, hyperarousal, and aversive facial expressions (AFEs) to social touch than to object touch, in both ASD models compared with controls. Fmr1 KO mice showed more AFEs to mice of the same sex but whether they were stranger or familiar mice mattered less. Because this new social touch assay for head-fixed mice can be used to record neural activity during repeated bouts of social touch it could be used to uncover underlying circuit differences.SIGNIFICANCE STATEMENT Social touch is important for communication in animals and humans. However, it has not been extensively studied and current assays to measure animals’ responses to social touch have limitations. We present a novel head-fixed assay to quantify how mice respond to social facial touch with another mouse. We validated this assay in autism mouse models since autistic individuals exhibit differences in social interaction and touch sensitivity. We find that mouse models of autism exhibit more avoidance, hyperarousal, and aversive facial expressions (AFEs) to social touch compared with controls. Thus, this novel assay can be used to investigate behavioral responses to social touch and the underlying brain mechanisms in rodent models of neurodevelopmental conditions, and to evaluate therapeutic responses in preclinical studies.

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5. Cuomo M, Coretti L, Costabile D, Della Monica R, De Riso G, Buonaiuto M, Trio F, Bravaccio C, Visconti R, Berni Canani R, Chiariotti L, Lembo F. Host fecal DNA specific methylation signatures mark gut dysbiosis and inflammation in children affected by autism spectrum disorder. Sci Rep;2023 (Oct 24);13(1):18197.

The gut-brain axis involves several bidirectional pathway communications including microbiome, bacterial metabolites, neurotransmitters as well as immune system and is perturbed both in brain and in gastrointestinal disorders. Consistently, microbiota-gut-brain axis has been found altered in autism spectrum disorder (ASD). We reasoned that such alterations occurring in ASD may impact both on methylation signatures of human host fecal DNA (HFD) and possibly on the types of human cells shed in the stools from intestinal tract giving origin to HFD. To test this hypothesis, we have performed whole genome methylation analysis of HFD from an age-restricted cohort of young children with ASD (N = 8) and healthy controls (N = 7). In the same cohort we have previously investigated the fecal microbiota composition and here we refined such analysis and searched for eventual associations with data derived from HFD methylome analysis. Our results showed that specific epigenetic signatures in human fecal DNA, especially at genes related to inflammation, associated with the disease. By applying methylation-based deconvolution algorithm, we found that the HFD derived mainly from immune cells and the relative abundance of those differed between patients and controls. Consistently, most of differentially methylated regions fitted with genes involved in inflammatory response. Interestingly, using Horvath epigenetic clock, we found that ASD affected children showed both epigenetic and microbiota age accelerated. We believe that the present unprecedented approach may be useful for the identification of the ASD associated HFD epigenetic signatures and may be potentially extended to other brain disorders and intestinal inflammatory diseases.

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6. Curatolo P, Scheper M, Emberti Gialloreti L, Specchio N, Aronica E. Is tuberous sclerosis complex-associated autism a preventable and treatable disorder?. World J Pediatr;2023 (Oct 25)

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 and TSC2 genes, causing overactivation of the mechanistic (previously referred to as mammalian) target of rapamycin (mTOR) signaling pathway in fetal life. The mTOR pathway plays a crucial role in several brain processes leading to TSC-related epilepsy, intellectual disability, and autism spectrum disorder (ASD). Pre-natal or early post-natal diagnosis of TSC is now possible in a growing number of pre-symptomatic infants. DATA SOURCES: We searched PubMed for peer-reviewed publications published between January 2010 and April 2023 with the terms « tuberous sclerosis », « autism », or « autism spectrum disorder », » animal models », « preclinical studies », « neurobiology », and « treatment ». RESULTS: Prospective studies have highlighted that developmental trajectories in TSC infants who were later diagnosed with ASD already show motor, visual and social communication skills in the first year of life delays. Reliable genetic, cellular, electroencephalography and magnetic resonance imaging biomarkers can identify pre-symptomatic TSC infants at high risk for having autism and epilepsy. CONCLUSIONS: Preventing epilepsy or improving therapy for seizures associated with prompt and tailored treatment strategies for autism in a sensitive developmental time window could have the potential to mitigate autistic symptoms in infants with TSC.

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7. Dhuliawala S, Payakachat N, Painter JT, Swindle T, Li C. Food Insecurity and Health Outcomes of Children With Intellectual and Developmental Disabilities in the United States. Am J Intellect Dev Disabil;2023 (Nov 1);128(6):462-480.

We aimed to (a) provide nationally representative estimates of food insecurity (FI) among children with intellectual and developmental disabilities (IDD), and (b) determine the association between FI and four health outcomes (overall health, problem behavior, activities of daily living, functional limitations) in 5,657 children with IDD compared to 1:1 propensity score matched children without IDD. Mixed-effects ordered logistic regression models were used. Children with IDD were more likely to experience FI than children without IDD (43.3% vs. 30.0%, p < 0.001). FI and IDD were independently associated with worse scores on all four health outcomes. Having both FI and IDD further exacerbated the adverse impacts on these health outcomes. The association was stronger among children with moderate-to-severe FI than those with mild FI.

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8. Mir A, Song Y, Lee H, Nadeali Z, Tabatabaiefar MA. A novel de novo frameshift variant in the CHD2 gene related to intellectual and developmental disability, seizures and speech problems. Mol Genet Genomic Med;2023 (Oct 25):e2305.

BACKGROUND: The chromodomain helicase DNA-binding protein 2 (CHD2) is a member of the ATP-dependent chromatin remodelling family of proteins, which are critical for the assembly and regulation of chromatin. De novo variants and deletions in the CHD2 gene have been associated with childhood-onset developmental and epileptic encephalopathies type 94 (DEE 94). This study reports a novel deleterious de novo heterozygous frameshift insertion variant in the CHD2 gene. METHODS: The causative variant was diagnosed using whole-exome sequencing. Sanger sequencing and cosegregation analysis were applied to confirm the candidate variant. Multiple in silico analysis tools were employed to interpret the variant using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS: A de novo deleterious variant, NM_001271.4:c.1570dup (NP_001262.3:p.Ser524PhefsTer30), in the CHD2 gene, was identified in a 16-year-old boy with an intellectual and developmental disability, seizures and speech problems. The de novo occurrence of the variant was confirmed by segregation analysis in the family. CONCLUSION: The findings of this study expand the existing knowledge of variants of the CHD2 gene and provide a detailed phenotype associated with this gene. These data could have implications for genetic diagnosis and counselling in similar conditions. Moreover, this information could be useful for therapeutic purposes, including the proper administration of medication to control epilepsy.

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9. Qin Y, Zhang XY, Liu Y, Ma Z, Tao S, Li Y, Peng R, Wang F, Wang J, Feng J, Qiu Z, Jin L, Wang H, Gong X. Downregulation of mGluR1-mediated signaling underlying autistic-like core symptoms in Shank1 P1812L-knock-in mice. Transl Psychiatry;2023 (Oct 25);13(1):329.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms that consist of social deficits and repetitive behaviors. Unfortunately, no effective medication is available thus far to target the core symptoms of ASD, since the pathogenesis remains largely unknown. To investigate the pathogenesis of the core symptoms in ASD, we constructed Shank1 P1812L-knock-in (KI) mice corresponding to a recurrent ASD-related mutation, SHANK1 P1806L, to achieve construct validity and face validity. Shank1 P1812L-KI heterozygous (HET) mice presented with social deficits and repetitive behaviors without the presence of confounding comorbidities. HET mice also exhibited downregulation of metabotropic glutamate receptor (mGluR1) and associated signals, along with structural abnormalities in the dendritic spines and postsynaptic densities. Combined with findings from Shank1 R882H-KI mice, our study confirms that mGluR1-mediated signaling dysfunction is a pivotal mechanism underlying the core symptoms of ASD. Interestingly, Shank1 P1812L-KI homozygous (HOM) mice manifested behavioral signs of impaired long-term memory rather than autistic-like core traits; thus, their phenotype was markedly different from that of Shank1 P1812L-KI HET mice. Correspondingly, at the molecular level, Shank1 P1812L-KI HOM displayed upregulation of AMPA receptor (GluA2)-related signals. The different patterns of protein changes in HOM and HET mice may explain the differences in behaviors. Our study emphasizes the universality of mGluR1-signaling hypofunction in the pathogenesis of the core symptoms in ASD, providing a potential target for therapeutic drugs. The precise correspondence between genotype and phenotype, as shown in HOM and HET mice, indicates the importance of reproducing disease-related genotypes in mouse models.

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10. Taylor MJ, van Leeuwen TM, Kuja-Halkola R, Lundström S, Larsson H, Lichtenstein P, Bölte S, Neufeld J. Genetic and environmental architecture of synaesthesia and its association with the autism spectrum-a twin study. Proc Biol Sci;2023 (Oct 25);290(2009):20231888.

Synaesthesia is a sensory phenomenon where external stimuli, such as sounds or letters, trigger additional sensations (e.g. colours). Synaesthesia aggregates in families but its heritability is unknown. The phenomenon is more common in people on the autism spectrum compared with the general population and associated with higher autistic traits. Using classical twin design, we assessed the heritability of individual differences in self-reported synaesthesia and the genetic and environmental contributions to their association with autistic traits within a population twin cohort (n = 4262, age = 18 years). We estimated individual differences in synaesthesia to be heritable and influenced by environmental factors not shared between twins. The association between individual differences in synaesthesia and autistic traits was estimated to be predominantly under genetic influence and seemed to be mainly driven by non-social autistic traits (repetitive behaviours, restricted interests and attention to detail). Our study suggests that the link between synaesthesia and autism might reside in shared genetic causes, related to non-social autistic traits such as alterations in perception. Future studies building on these findings may attempt to identify specific groups of genes that influence both autism, synaesthesia and perception.

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