1. Andreo-Martínez P, Rubio-Aparicio M, Sánchez-Meca J, Veas A, Martínez-González AE. A Meta-analysis of Gut Microbiota in Children with Autism. Journal of autism and developmental disorders. 2022; 52(3): 1374-87.

Previous studies have reported dysbiosis in the gut microbiota (GM) of children with autism spectrum disorders (ASD), which may be a determining factor on child development through the microbiota-gut-brain axis. However, it is not clear if there is a specific group of dysbiotic bacteria in ASD. The aim of this study was to carry out a meta-analysis on the studies that analyze GM in children with ASD. 18 studies fulfilled our selection criteria. Our results showed a lower relative abundance of Streptococcus (SMD(+) = - 0.999; 95% CI – 1.549, – 0.449) and Bifidobacterium genera (SMD(+) = - 0.513; 95% CI – 0.953, – 0.073) in children with ASD. Overall, the Bifidobacterium genera is involved. However, differences found between studies are attributed to factors such as reporting bias.

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2. Bellone C, Lüscher C. Bugs R Us: Restoring sociability with microbiota in autism. Cell reports Medicine. 2021; 2(4): 100256.

In a recent publication in Cell, Buffington et al. provide a fascinating example of hologenomic behavioral regulation in an autism mouse model.(1) The authors report that gut bacteria from wild-type mice rescue the social deficit of Cntnap2 knockout mice.

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3. Brown M, Marsh L, McCann E. Experiences of fathers regarding the diagnosis of their child with autism spectrum disorder: A narrative review of the international research. Journal of clinical nursing. 2021; 30(19-20): 2758-68.

AIM AND OBJECTIVES: The aim of this systematic review was to identify the views and experiences of fathers regarding their child’s Autism Spectrum Disorder diagnosis. BACKGROUND: The diagnosis of a child’s Autism Spectrum Disorder may be a stressful experience, creating uncertainty for parents. There has been a limited research focus on the views and experiences of fathers in relation to the diagnosis of Autism Spectrum Disorder of their child. DESIGN: A systematic literature review of quantitative, qualitative and mixed-methods research studies. DATA SOURCES: Academic Search Complete, CINAHL, MEDLINE and PsycINFO. METHODS: From August to October 2020, two authors independently performed a systematic data extraction and appraised the studies using a recognised instrument. The PRISMA checklist was used in the review. RESULTS: Nine papers met the inclusion criteria. Four themes emerged: (a) gradual recognition of developmental delay, (b) an emotional time, (c) coping and adaptation and (d) ongoing adjustments to the fathering role. CONCLUSIONS: Nurses and other professionals need to work collaboratively with fathers to improve their experiences and provide supports at the time of Autism Spectrum Disorder diagnosis.

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4. Chermnykh ES, Schepetov DM, Vorotelyak EA. Wal Mutant Mice Have a Mutation Associated with Autism Spectrum Disorders. Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections. 2021; 497(1): 59-61.

The waved alopecia (wal) mutation arose spontaneously in mice. Phenotypically, the wal mutation in a homozygous recessive state is manifested by a wavy coat. Over time, partial baldness develops, which leads to a thinning of the coat in mice. The molecular nature of the genetic defect in wal is still unknown; however, the coordinates of the chromosome locus in which the wal gene is located, a section of about 10(7) bp in length, has been determined in mouse chromosome 14. We examined the wal locus by sequencing the exons of candidate genes in which the mutation was expected, and performed genome-wide sequencing to identify the cause of the wal mutation. The sequences of exons of candidate genes located in this region did not carry changes that could lead to a change in the structure of the protein. However, outside the wal zone, a mutation in the Slc9a9 gene was found that is probably not associated with the wal phenotype. According to the literature, a mutation in the Slc9a9 gene leads to autism spectrum disorders. This is the first discovered spontaneous mutation in the Slc9a9 gene in mice.

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5. Costa L, Tempio A, Lacivita E, Leopoldo M, Ciranna L. Serotonin 5-HT7 receptors require cyclin-dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome. The European journal of neuroscience. 2021; 54(1): 4124-32.

Fragile X Syndrome is a genetic form of intellectual disability associated with autism, epilepsy and mood disorders. Electrophysiology studies in Fmr1 knockout (KO) mice, a murine model of Fragile X Syndrome, have demonstrated alterations of synaptic plasticity, with exaggerated long-term depression induced by activation of metabotropic glutamate receptors (mGluR-LTD) in Fmr1 KO hippocampus. We have previously demonstrated that activation of serotonin 5-HT7 receptors reverses mGluR-LTD in the hippocampus of wild-type and Fmr1 KO mice, thus correcting a synaptic dysfunction typically observed in this disease model. Here we show that pharmacological inhibition of cyclin-dependent kinase 5 (Cdk5, a signaling molecule recently shown to be a modulator of brain synaptic plasticity) enhanced mGluR-LTD in wild-type hippocampal neurons, which became comparable to exaggerated mGluR-LTD observed in Fmr1 KO neurons. Furthermore, Cdk5 inhibition prevented 5-HT7 receptor-mediated reversal of mGluR-LTD both in wild-type and in Fmr1 KO neurons. Our results show that Cdk5 modulates hippocampal synaptic plasticity. 5-HT7 receptors require Cdk5 to modulate synaptic plasticity in wild-type and rescue abnormal plasticity in Fmr1 KO neurons, pointing out Cdk5 as a possible novel target in Fragile X Syndrome.

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6. Georgiou N, Spanoudis G. Developmental Language Disorder and Autism: Commonalities and Differences on Language. Brain sciences. 2021; 11(5).

Language and communication deficits characterize both autism spectrum disorder and developmental language disorder, and the possibility of there being a common profile of these is a matter of tireless debate in the research community. This experimental study addresses the relation of these two developmental conditions in the critical topic of language. Α total of 103 children (79 males, 24 females) participated in the present study. Specifically, the study’s sample consisted of 40 children with autism, 28 children with developmental language disorder, and 35 typically developing children between 6 and 12 years old. All children completed language and cognitive measures. The results showed that there is a subgroup inside the autism group of children who demonstrate language difficulties similar to children with developmental language disorder. Specifically, two different subgroups were derived from the autism group; those with language impairment and those without. Both autism and language-impaired groups scored lower than typically developing children on all language measures indicating a common pathology in language ability. The results of this study shed light on the relation between the two disorders, supporting the assumption of a subgroup with language impairment inside the autism spectrum disorder population. The common picture presented by the two developmental conditions highlights the need for further research in the field.

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7. He H, Guzman RE, Cao D, Sierra-Marquez J, Yin F, Fahlke C, Peng J, Stauber T. The molecular and phenotypic spectrum of CLCN4-related epilepsy. Epilepsia. 2021; 62(6): 1401-15.

OBJECTIVE: This study was undertaken to expand the phenotypic and genetic spectrum of CLCN4-related epilepsy and to investigate genotype-phenotype correlations. METHODS: We systematically reviewed the phenotypic and genetic spectrum of newly diagnosed and previously reported patients with CLCN4-related epilepsy. Three novel variants identified in four patients reported in this study were evaluated through in silico prediction and functional analysis by Western blot, immunofluorescence, and electrophysiological measurements. RESULTS: Epilepsy was diagnosed in 54.55% (24/44) of individuals with CLCN4-related disorders and was drug-resistant in most cases. Of 24 patients, 15 had epileptic encephalopathy and four died at an early age; 69.57% of patients had seizure onset within the first year of life. Myoclonic seizures are the most common seizure type, and 56.25% of patients presented multiple seizure types. Notably, seizure outcome was favorable in individuals with only one seizure type. All patients showed intellectual disability, which was severe in 65.22% of patients. Additional common features included language delay, behavioral disorders, and dysmorphic features. Five patients benefitted from treatment with lamotrigine. Most variants, which were mainly missense (79.17%), were inherited (70.83%). Whereas frameshift, intragenic deletion, or inherited variants were associated with milder phenotypes, missense or de novo variants led to more severe phenotypes. All evaluated CLCN4 variants resulted in loss of function with reduced ClC-4 currents. Nonetheless, genotype-phenotype relationships for CLCN4-related epilepsy are not straightforward, as phenotypic variability was observed in recurrent variants and within single families. SIGNIFICANCE: Pathogenic CLCN4 variants contribute significantly to the genetic etiology of epilepsy. The phenotypic spectrum of CLCN4-related epilepsy includes drug-resistant seizures, cognitive and language impairment, behavioral disorders, and congenital anomalies. Notably, the mutation type and the number of seizure types correlate with the severity of the phenotype, suggesting its use for clinical prognosis. Lamotrigine can be considered a therapeutic option.

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8. Heavner WE, Lautz JD, Speed HE, Gniffke EP, Immendorf KB, Welsh JP, Baertsch NA, Smith SEP. Remodeling of the Homer-Shank interactome mediates homeostatic plasticity. Science signaling. 2021; 14(681).

Neurons maintain stable levels of excitability using homeostatic synaptic scaling, which adjusts the strength of a neuron’s postsynaptic inputs to compensate for extended changes in overall activity. Here, we investigated whether prolonged changes in activity affect network-level protein interactions at the synapse. We assessed a glutamatergic synapse protein interaction network (PIN) composed of 380 binary associations among 21 protein members in mouse neurons. Manipulating the activation of cultured mouse cortical neurons induced widespread bidirectional PIN alterations that reflected rapid rearrangements of glutamate receptor associations involving synaptic scaffold remodeling. Sensory deprivation of the barrel cortex in live mice (by whisker trimming) caused specific PIN rearrangements, including changes in the association between the glutamate receptor mGluR5 and the kinase Fyn. These observations are consistent with emerging models of experience-dependent plasticity involving multiple types of homeostatic responses. However, mice lacking Homer1 or Shank3B did not undergo normal PIN rearrangements, suggesting that the proteins encoded by these autism spectrum disorder-linked genes serve as structural hubs for synaptic homeostasis. Our approach demonstrates how changes in the protein content of synapses during homeostatic plasticity translate into functional PIN alterations that mediate changes in neuron excitability.

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9. Kitchin JL, Karlin NJ. Awareness and Stigma of Autism Spectrum Disorders in Undergraduate Students. Psychological reports. 2021: 332941211014144.

BACKGROUND: Social stigma is a barrier for students with autism on college campuses. The purpose of this study is to examine the relationship between autism knowledge and autism stigma endorsement. METHOD: 144 college undergraduate students were asked to complete the Autism Stigma and Knowledge Questionnaire as well as a brief demographic questionnaire. The relationship between stigma endorsement and ASD knowledge in the areas of diagnosis and symptoms, etiology, and treatment were evaluated using a multiple linear regression. Two independent-sample t-tests were conducted to investigate group differences between participants who know someone with autism and those who do not as well as between male and female participants. RESULTS: A significant regression equation was found (F(3,140) = 51.35, p = .000), with an R(2) of .52. While Treatment and Etiology subscale scores significantly predicted Stigma subscale scores, Diagnosis/Symptom subscale score was not. In terms of knowing someone with an autism diagnosis, there was a significant difference in ASD diagnosis and symptom knowledge (t(142) = 4.16, p = .000), etiology knowledge (t(142) = 3.51, p = .001), treatment knowledge (t(62.99) = 3.54, p = .001), and stigma endorsement (t(142) = 3.03, p = .003). No significant differences were found between male and female participants. CONCLUSIONS: Contrary to past studies, gender was not associated with ASD knowledge or stigma endorsement. This study suggests that an intervention designed to increase ASD knowledge, particularly in the areas of etiology and treatment, and to increase contact with students diagnosed with autism would be effective in reducing ASD stigma.

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10. Lian F, Northoff G. The Lost Neural Hierarchy of the Autistic Self-Locked-Out of the Mental Self and Its Default-Mode Network. Brain sciences. 2021; 11(5).

Autism spectrum disorder (ASD) is characterized by a fundamental change in self-awareness including seemingly paradoxical features like increased ego-centeredness and weakened self-referentiality. What is the neural basis of this so-called « self-paradox »? Conducting a meta-analytic review of fMRI rest and task studies, we show that ASD exhibits consistent hypofunction in anterior and posterior midline regions of the default-mode network (DMN) in both rest and task with decreased self-non-self differentiation. Relying on a multilayered nested hierarchical model of self, as recently established (Qin et al. 2020), we propose that ASD subjects cannot access the most upper layer of their self, the DMN-based mental self-they are locked-out of their own DMN and its mental self. This, in turn, results in strong weakening of their self-referentiality with decreases in both self-awareness and self-other distinction. Moreover, this blocks the extension of non-DMN cortical and subcortical regions at the lower layers of the physical self to the DMN-based upper layer of the mental self, including self-other distinction. The ASD subjects remain stuck and restricted to their intero- and exteroceptive selves as manifested in a relative increase in ego-centeredness (as compared to self-referentiality). This amounts to what we describe as « Hierarchical Model of Autistic Self » (HAS), which, characterizing the autistic self in hierarchical and spatiotemporal terms, aligns well with and extends current theories of ASD including predictive coding and weak central coherence.

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11. López-Florit L, García-Cuesta E, Gracia-Expósito L, García-García G, Iandolo G. Physiological Reactions in the Therapist and Turn-Taking during Online Psychotherapy with Children and Adolescents with Autism Spectrum Disorder. Brain sciences. 2021; 11(5).

This study aims to analyze the relationship between the sociocognitive skills of a group of children and adolescents with autism spectrum disorder (ASD) at verbal level 1, the variability of the therapist’s heart rate (HRV), and the conversational turn-taking during online psychotherapy sessions. Initially, we assessed the intelligence, narrative, and behavioral characteristics of the participants. We videotaped the online sessions and recorded the therapist’s HRV via a smart wireless sensor. Finally, we analyzed the video sessions using an observation system and the therapist’s HRV using the Poincaré technique. The results show that the patients’ communicative intention was related to their narrative, intellectual and social competencies. Furthermore, the turn-taking between the therapist and the participant was associated with the patient’s emotional and behavioral difficulties. On the other side, the therapist’s heart rate variability (HRV) was related to the synchrony between the therapist and the participant with more significant stress on the therapist, when he shared and expanded the conversation with the patient, and when the patient broadened and shared the conversation with the therapist.

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12. Marciano H, Gal E, Kimchi R, Hedley D, Goldfarb Y, Bonneh YS. Visual Detection and Decoding Skills of Aerial Photography by Adults with Autism Spectrum Disorder (ASD). Journal of autism and developmental disorders. 2022; 52(3): 1346-60.

Despite challenges in social communication skills people with ASD often display strengths in visual processing. Aerial photography analysis is an occupation reliant on strong visual processing skills that matches this unique profile. We investigated basic-vision and « real-life » visual tasks in 20 cognitively-able young adults with ASD and 20 typically-developed (TD) « gamers ». Basic-vision tests included Visual-Search, Embedded-Figures, and Vigilance; « real-life » tests included aerial-photograph detection and identification. Groups performed equally well, and did not differ significantly on any tasks. The study demonstrates strong visual skills in people with ASD in basic and « real-life » settings, and supports the idea that they may be well suited for employment in occupations that demand high visual perception skills such as aerial photography analysis.

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13. Oliveira BMF, Frutuoso MFP. [Far beyond nutrients: experiences and connections with autistic children based on cooking and sharing meals]. Cadernos de saude publica. 2021; 37(4): e00132020.

This study examined ways to expand the analysis of diet in autistic children, widely considered inadequate according to food selectivity and/or difficulty interacting at mealtimes, attributed to alterations in sensorial processing and social, communicative, and cognitive difficulties. From an ethnographic perspective, a participant observational study was performed with field diary records and cooking workshops with autistic children and adolescents, aimed at analyzing the relations established by the children with the food and utensils, physical space, and between each other and the adults. The records were analyzed based on Bondía’s notion of experience and Actor-Network Theory. The resulting data showed singularities in performing cooking tasks and accepting recipes. Some children did not eat the foods, but smelled, licked, and handled the ingredients in moments of experimentation through mediation by the educators, facilitating connection by the children with food and eating. The interactions established with foods and utensils highlight the importance of food and eating as mediators of the connection between autistic children and their peers, with adults, and with the world. This experience broke with the homogenizing value assigned to autistic children’s difficulties with interaction and reinforced commensality as a tool for building networks of care. To conceive eating for these children from an expanded perspective means to value subjectivity, the relationship to food, and interaction with others at mealtimes, far beyond the biological understanding of the nutrients.

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14. Pham HTN, Tran HN, Le XT, Do HT, Nguyen TT, Le Nguyen C, Yoshida H, Yamaguchi M, William FR, Matsumoto K. Ilex kudingcha C.J. Tseng Mitigates Phenotypic Characteristics of Human Autism Spectrum Disorders in a Drosophila Melanogaster Rugose Mutant. Neurochemical research. 2021; 46(8): 1995-2007.

Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Tseng is a nootropic botanical used in Asia for neuroprotection and improvement of cognition. This study establishes that a chemically characterized extract from IK (IKE) mitigates behavioral traits in the Drosophila melanogaster rugose mutant, whose traits resemble human ASD, and examines possible mechanisms. IKE treatment significantly ameliorated deficits in social interaction, short-term memory, and locomotor activity in Drosophila rugose, and significantly increased synaptic bouton number of size more than 2 μm(2) in the neuromuscular junctions (NMJs) of Drosophila rugose. To clarify mechanism(s) of IKE action, methylphenidate (MPH), a dopamine transporter inhibitor, was included as a reference drug in the behavioral assays: MPH significantly improved social interaction and short-term memory deficit in Drosophila rugose; administration of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist sulpiride reversed the ameliorative effects of both MPH and IKE on the social interaction deficits of Drosophila rugose. To extend analysis of IKE treatment to the vertebrate central nervous system, ASD-associated gene expression in mouse hippocampus was studied by RNA-seq: IKE treatment altered the expression of genes coding phosphoinositide 3-kinases/protein kinase B (PI3K-Akt), proteins in glutamatergic, dopaminergic, serotonergic, and GABAergic synapses, cAMP response element-binding protein (CREB), and RNA transporter proteins. These results provide a foundation for further analysis of IKE as a candidate for treatment of some forms of ASD.

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15. Sinnett SE, Boyle E, Lyons C, Gray SJ. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain : a journal of neurology. 2021; 144(10): 3005-19.

MECP2 gene transfer has been shown to extend the survival of Mecp2-/y knockout mice modelling Rett syndrome, an X-linked neurodevelopmental disorder. However, controlling deleterious overexpression of MECP2 remains the critical unmet obstacle towards a safe and effective gene therapy approach for Rett syndrome. A recently developed truncated miniMECP2 gene has also been shown to be therapeutic after AAV9-mediated gene transfer in knockout neonates. We show that AAV9/miniMECP2 has a similar dose-dependent toxicity profile to that of a published second-generation AAV9/MECP2 vector after treatment in adolescent mice. To overcome that toxicity, we developed a risk-driven viral genome design strategy rooted in high-throughput profiling and genome mining to rationally develop a compact, synthetic microRNA target panel (miR-responsive auto-regulatory element, ‘miRARE’) to minimize the possibility of miniMECP2 transgene overexpression in the context of Rett syndrome gene therapy. The goal of miRARE is to have a built-in inhibitory element responsive to MECP2 overexpression. The data provided herein show that insertion of miRARE into the miniMECP2 gene expression cassette greatly improved the safety of miniMECP2 gene transfer without compromising efficacy. Importantly, this built-in regulation system does not require any additional exogenous drug application, and no miRNAs are expressed from the transgene cassette. Although broad applications of miRARE have yet to be determined, the design of miRARE suggests a potential use in gene therapy approaches for other dose-sensitive genes.

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16. Uddin MS, Azima A, Aziz MA, Aka TD, Jafrin S, Millat MS, Siddiqui SA, Uddin MG, Hussain MS, Islam MS. CNTNAP2 gene polymorphisms in autism spectrum disorder and language impairment among Bangladeshi children: a case-control study combined with a meta-analysis. Human cell. 2021; 34(5): 1410-23.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by communication deficits, impaired social interactions, repetitive and stereotyped behaviors with restricted interests, and connected with the interaction between environmental factors and genetic vulnerability. CNTNAP2 gene has been extensively investigated for ASD and related neurodevelopment diseases. However, previous studies have resulted in an inconsistent outcome. Based on this fact, we conducted a case-control study followed by a meta-analysis to investigate the association of rs7794745 and rs2710102 polymorphisms with ASD. A total of 216 autistic children and 240 healthy volunteers were recruited, and genotyping was performed using the PCR-RFLP method. We observed that SNP rs7794745 revealed a significantly (p < 0.05) increased association with the development of ASD in children in all genetic models. No significant association was found for rs2710102 with ASD. Besides, rs2710102 exhibited a significant association with language impairment in TC genotype, C allele, and dominant model. From the meta-analysis of both SNPs, we found a significant association in codominant 1, 2, and the dominant model of rs2710102 and codominant 1 and dominant model of rs7794745 with ASD. Our case-control study suggests that rs7794745 polymorphism is associated with ASD, while rs2710102 is correlated with language impairment. Moreover, meta-analysis results indicated the association between both rs7794745 and rs2710102 polymorphisms and ASD.

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17. Wilkinson KM, O’Neill Zimmerman T, Light J. Visual Attention to Cued Targets in Simulated Aided Augmentative and Alternative Communication Displays for Individuals With Intellectual and Developmental Disabilities. Journal of speech, language, and hearing research : JSLHR. 2021; 64(5): 1726-38.

Purpose Many aided augmentative and alternative communication (AAC) systems require the use of an external display that is represented via a visual modality. It is critical to evaluate and understand visual-perceptual processing in individuals with disabilities who could benefit from AAC. One way to evaluate how individuals process visual materials is through research-based automated eye-tracking technologies that obtain a fine-grained stream of data concerning gaze paths of visual attention. Method The current study examined how individuals with autism spectrum disorder (n = 13), Down syndrome (n = 13), intellectual and developmental disabilities (n = 9), or typical development (n = 20) responded to a spoken prompt to find a thumbnail-sized navigation key within a complex AAC display, including a main visual scene display (VSD) and a navigation bar of four thumbnail-sized VSDs. Stimuli were presented on a monitor containing automated eye-tracking research technology that recorded patterns of visual attention. Results Participants across groups spent more time fixating on a target thumbnail VSD navigation image after the presentation of the spoken cue to look at the target, compared to before the presentation of the spoken cue; they also spent more time looking at the target thumbnail VSD than the other thumbnail-sized VSDs in the navigation bar after the cue. Discussion Participants were able to locate the target thumbnail VSDs, even within the context of a visually complex AAC display. Implications for the design of AAC displays and for assessment of comprehension are discussed.

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18. Zhang R, He H, Yuan B, Wu Z, Wang X, Du Y, Chen Y, Qiu Z. An Intronic Variant of CHD7 Identified in Autism Patients Interferes with Neuronal Differentiation and Development. Neuroscience bulletin. 2021; 37(8): 1091-106.

Genetic composition plays critical roles in the pathogenesis of autism spectrum disorder (ASD). Especially, inherited and de novo intronic variants are often seen in patients with ASD. However, the biological significance of intronic variants is difficult to address. Here, among a Chinese ASD cohort, we identified a recurrent inherited intronic variant in the CHD7 gene, which is specifically enriched in East Asian populations. CHD7 has been implicated in numerous developmental disorders including CHARGE syndrome and ASD. To investigate whether the ASD-associated CHD7 intronic variant affects neural development, we established human embryonic stem cells carrying this variant using CRISPR/Cas9 methods and found that the level of CHD7 mRNA significantly decreased compared to control. Upon differentiation towards the forebrain neuronal lineage, we found that neural cells carrying the CHD7 intronic variant exhibited developmental delay and maturity defects. Importantly, we found that TBR1, a gene also implicated in ASD, was significantly increased in neurons carrying the CHD7 intronic variant, suggesting the intrinsic relevance among ASD genes. Furthermore, the morphological defects found in neurons carrying CHD7 intronic mutations were rescued by knocking down TBR1, indicating that TBR1 may be responsible for the defects in CHD7-related disorders. Finally, the CHD7 intronic variant generated three abnormal forms of transcripts through alternative splicing, which all exhibited loss-of-function in functional assays. Our study provides crucial evidence supporting the notion that the intronic variant of CHD7 is potentially an autism susceptibility site, shedding new light on identifying the functions of intronic variants in genetic studies of autism.

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