1. de Boer E, Yaldiz B, Denommé-Pichon AS, Matalonga L, Laurie S. Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant. European journal of medical genetics. 2022; 65(1): 104402.

Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wide variant calling approach, despite being located in protein coding sequence. More detailed analysis revealed that the position of the variant within exon 5 of TUBB3 was not targeted by the enrichment kit, although consistent high-quality coverage was obtained at this position, resulting from nearby targets that provide off-target coverage. In the initial analysis, variant calling was restricted to the exon targets ± 200 bases, allowing the variant to escape detection by the variant calling algorithm. This phenomenon may potentially occur more often, as we determined that 36 established ID genes have robust off-target coverage in coding sequence. Moreover, within these regions, for 17 genes (likely) pathogenic variants have been identified before. Therefore, this clinical report highlights that, although compute-intensive, performing genome-wide variant calling instead of target-based calling may lead to the detection of diagnostically relevant variants that would otherwise remain unnoticed.

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2. Gridina MM, Shitik EM, Lemskaya NA, Minina JM, Grishchenko IV, Dolskiy AA, Shorina AR, Maksimova YV, Yudkin DV. Derivation of iPS cell line (ICGi032-A) from a patient affected with fragile X syndrome. Stem cell research. 2021; 57: 102615.

Trinucleotide repeat expansion diseases such as fragile X syndrome are of great interest to study since the mechanism of its development is still unknown. IPS cell lines are some of the most convenient models for studying. The ICGi032-A iPS cell line was obtained from the peripheral blood mononuclear cells of the patient affected with fragile X syndrome. ICGi032-A iPS cell line have a normal karyotype, expression of pluripotency markers and can differentiate in vitro into the cells of three germ layers.

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3. Guillory SB, Baskett VZ, Grosman HE, McLaughlin CS, Isenstein EL, Wilkinson E, Weissman J, Britvan B, Trelles MP, Halpern DB, Buxbaum JD, Siper PM, Wang AT, Kolevzon A, Foss-Feig JH. Social visual attentional engagement and memory in Phelan-McDermid syndrome and autism spectrum disorder: a pilot eye tracking study. Journal of neurodevelopmental disorders. 2021; 13(1): 58.

BACKGROUND: The current study used eye tracking to investigate attention and recognition memory in Phelan-McDermid syndrome (PMS), a rare genetic disorder characterized by intellectual disability, motor delays, and a high likelihood of comorbid autism spectrum disorder (ASD). Social deficits represent a core feature of ASD, including decreased propensity to orient to or show preference for social stimuli. METHODS: We used a visual paired-comparison task with both social and non-social images, assessing looking behavior to a novel image versus a previously viewed familiar image to characterize social attention and recognition memory in PMS (n = 22), idiopathic ASD (iASD, n = 38), and typically developing (TD) controls (n = 26). The idiopathic ASD cohort was divided into subgroups with intellectual disabilities (ID; developmental quotient < 70) and without (developmental quotient > 70) and the PMS group into those with and without a co-morbid ASD diagnosis. RESULTS: On measures of attention, the PMS group with a comorbid ASD diagnosis spent less time viewing the social images compared to non-social images; the rate of looking back and forth between images was lowest in the iASD with ID group. Furthermore, while all groups demonstrated intact recognition memory when novel non-social stimuli were initially presented (pre-switch), participants with PMS showed no preference during the post-switch memory presentation. In iASD, the group without ID, but not the group with ID, showed a novelty preference for social stimuli. Across indices, individuals with PMS and ASD performed more similarly to PMS without ASD and less similarly to the iASD group. CONCLUSION: These findings demonstrate further evidence of differences in attention and memory for social stimuli in ASD and provide contrasts between iASD and PMS.

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4. Jia YN, Gu JH, Wei QL, Jing YZ, Gan XY, Du XZ. [Effect of scalp acupuncture stimulation on mood and sleep in children with autism spectrum disorder]. Zhen ci yan jiu = Acupuncture research. 2021; 46(11): 948-52.

OBJECTIVE: To observe the effects of penetrating technique of scalp acupuncture on emotion, sleep and function development in children of autism spectrum disorder (ASD). METHODS: A total of 60 SAD children aged 3 to 6 years were randomized in a control group (music education rehabilitation,n=30) and an observation group (penetrating technique of scalp acupuncture + music education rehabilitation,n=30). In the two groups, the treatment for 3 months was as 1 course, and 2 courses of treatment were required. Before and after treatment, the changes were observed in childhood autism rating scale (CARS), emotion regulation subscale (ER), children’s sleep habits questionnaire (CSHQ) and children autism and psycho-educational profile for autistic and developmentally disabled children (C-PEP-3), separately. RESULTS: Compared with the scores before treatment, CARS score, the score of each subscale of CSHQ, e.g. bedtime resistance, sleep onset delay, irregular sleep duration, sleep anxiety, parasomnias and daytime sleepiness as well as the total score of CSHQ were all reduced in children of two groups (P<0.05); and the score of ER and C-PEP-3 were all increased (P<0.05) after 6 months' treatment. Compared with the control group, ER score was increased in 3 and 6 months after treatment (P<0.05), CARS score was reduced (P<0.05) and C-PEP-3 score was increased obviously (P<0.05) 6 months after treatment in the observation group; but the scores of the subscale for night waking and sleep disordered breathing did not changed noticeably (P > 0.05). CONCLUSION: Penetrating technique of scalp acupuncture improves the emotion and sleep disorder and promotes the function development in ASD children.

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5. Ku B, Jin J. Understanding parental physical activity support in parents of children with developmental disabilities across two different countries. Research in developmental disabilities. 2022; 120: 104140.

BACKGROUND: It remains unclear if there is a difference between parental physical activity (PA) support in parents of children with developmental disabilities (DDs) and parental PA support in parents of children without DDs across countries. AIMS: The purposes of the current study were to examine parental PA support in parents of children with and without DDs from the United States and South Korea and to examine their parental PA support mechanism based on the theory of planned behavior (TPB). METHODS AND PROCEDURES: An online survey was used to measure demographic information, parental PA support, and four constructs of TPB in parents with and without DDs in the two countries (n = 277). One-way analysis of variance was used to compare parental PA support and the TPB constructs among the participants. Two separate path analyses were performed to examine associations between the TPB constructs and parental PA support in American parents of children with and without disabilities and South Korean parents of children with and without disabilities. OUTCOMES AND RESULTS: Parental PA support was significantly higher in American parents of children with DDs than in South Korean parents of children with DDs. Intention was significantly associated with parental PA support, and attitude was the strongest predictor for intention in both pathway models. CONCLUSIONS AND IMPLICATIONS: The difference in parental PA support between American parents of children with DDs and South Korean parents of children with DDs may exist. TPB-based intervention may be necessary in order to increase low parental PA support in South Korean parents of children with DDs.

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6. Lamba N, Van Tonder A, Shrivastava A, Raghavan A. Exploring challenges and support structures of mothers with children with Autism Spectrum Disorder in the United Arab Emirates. Research in developmental disabilities. 2022; 120: 104138.

BACKGROUND: Mothers with children with ASD, often being primary caregivers, experience high levels of parenting stress and hold essential information about their children’s wellbeing. There is however lack of information about their experiences in the UAE. AIMS: The study aims to explore challenges and support structures of mothers with children with ASD in the UAE. METHODS AND PROCEDURES: 17 expat mothers (Age (range) = 33-58 years) with a child with ASD were interviewed about their experiences with diagnoses, therapeutic interventions, support networks, and the pandemic. OUTCOMES AND RESULTS: Thematic analysis showed that initially most mothers struggled with accessing information to seek correct diagnoses, admission in mainstream international schools with typically developing children, and finding appropriate therapeutic services. Several mothers narrated experiences of not receiving optimum support from their partners, feeling rejected from extended family members, and facing hardships during the pandemic. Majority however appeared to be extremely satisfied with support groups where they felt heard and exchanged experience-based information crucial for children’s wellbeing. CONCLUSIONS AND IMPLICATIONS: Findings highlight the need for the government to facilitate centralized channels of information for expat parents with children with developmental disabilities, formalizing more support groups for mothers in the UAE, and increasing knowledge about autism to decrease biases.

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7. Loomes R, Bryant-Waugh R. Widening the reach of family-based interventions for Anorexia Nervosa: autism-adaptations for children and adolescents. Journal of eating disorders. 2021; 9(1): 157.

Family-based interventions are widely recommended as a first line treatment for children and young people with Anorexia Nervosa. There is clear evidence that model-adherent delivery of specific eating disorder focused family interventions has the potential to help adolescents with Anorexia Nervosa, who have typically engaged in extreme dietary restriction and lost a significant amount of weight over a relatively short period of time. Nevertheless, there remains a significant number of young people with restrictive eating disorders for whom family-based interventions for Anorexia Nervosa prove less effective, suggesting adaptations may be indicated for some. In this paper we provide a rationale and structure for considering a number of possible adaptations to the delivery of family-based therapy for anorexia nervosa specifically intended to enhance its relevance and potential effectiveness for children and adolescents on the autism spectrum; a subgroup known to represent a significant minority in eating disorder populations who have been identified as having relatively poor outcomes. Past research has shown that certain family-based treatments are effective for many children and adolescents who develop Anorexia Nervosa. At the same time this type of treatment approach in its current form does not work for everyone. Recent research has highlighted the overlap between anorexia and autism and the need for the development of adaptations to existing treatments to better meet the requirements of people on the autism spectrum who develop anorexia. With this in mind we propose a number of autism-related adaptations that could be made to family-based treatments for anorexia. We hope that these might be formally tested in the future to see if these adaptations improve outcomes for this group of individuals.

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8. Okano H, Takashima K, Takahashi Y, Ojiro R, Tang Q, Ozawa S, Ogawa B, Koyanagi M, Maronpot RR, Yoshida T, Shibutani M. Ameliorating effect of continuous alpha-glycosyl isoquercitrin treatment starting from late gestation in a rat autism model induced by postnatal injection of lipopolysaccharides. Chemico-biological interactions. 2022; 351: 109767.

The present study investigated the role of neuroinflammation and brain oxidative stress induced by neonatal treatment with lipopolysaccharides (LPS) on the development of autism spectrum disorder (ASD)-like behaviors and disruptive hippocampal neurogenesis in rats by exploring the chemopreventive effects of alpha-glycosyl isoquercitrin (AGIQ) as an antioxidant. AGIQ was dietary administered to dams at 0.25% or 0.5% (w/w) from gestational day 18 until postnatal day (PND) 21 on weaning and then to pups until the adult stage on PND 77. The pups were intraperitoneally injected with LPS (1 mg/kg body weight) on PND 3. At PND 6, LPS alone increased Iba1(+) and CD68(+) cell numbers without changing the CD163(+) cell number and strongly upregulated pro-inflammatory cytokine gene expression (Il1a, Il1b, Il6, Nfkb1, and Tnf) in the hippocampus, and increased brain malondialdehyde levels. At PND 10, pups decreased ultrasonic vocalization (USV), suggesting the induction of pro-inflammatory responses and oxidative stress to trigger communicative deficits. By contrast, LPS alone upregulated Nfe2l2 expression at PND 6, increased Iba1(+), CD68(+), and CD163(+) cell numbers, and upregulated Tgfb1 at PND 21, suggesting anti-inflammatory responses until the weaning period. However, LPS alone disrupted hippocampal neurogenesis at weaning and suppressed social interaction parameters and rate of freezing time at fear acquisition and extinction during the adolescent stage. On PND 77, neuroinflammatory responses had mostly disappeared; however, disruptive neurogenesis and fear memory deficits were sustained. AGIQ ameliorated most changes on acute pro-inflammatory responses and oxidative stress at PND 6, and the effects on USVs at PND 10 and neurogenesis and behavioral parameters throughout the adult stage. These results suggested that neonatal LPS treatment induced acute but transient neuroinflammation, triggering the progressive disruption of hippocampal neurogenesis leading to abnormal behaviors in later life. AGIQ treatment was effective for ameliorating LPS-induced progressive changes by critically suppressing initial pro-inflammatory responses and oxidative stress.

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9. Wang H, Jiang X, De Leone R, Zhang Y, Qiao L, Zhang L. Extracting BOLD signals based on time-constrained multiset canonical correlation analysis for brain functional network estimation and classification. Brain research. 2022; 1775: 147745.

Brain functional network (BFN), usually estimated from blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), has been proven to be a powerful tool to study the organization of the brain and discover biomarkers for diagnosis of brain disorders. Prior to BFN estimation and classification, extracting representative BOLD signals from brain regions of interest (ROIs) is a critical step. Traditional extraction methods include averaging, peaking operation and dimensionality reduction, often leading to signal cancellation and information loss. In this paper, we propose a novel method, namely time-constrained multiset canonical correlation analysis (TMCCA), to extract representative BOLD signals for subsequent BFN estimation and classification. Different from traditional methods that equally treat all BOLD signals in a ROI, the proposed method assigns weights to different BOLD signals, and learns the optimal weights to make the extracted representative signals jointly maximize the multiple correlations between ROIs. Importantly, time-constraint is incorporated into our proposed method, which can effectively encode nonlinear relationship among BOLD signals. To evaluate the effectiveness of the proposed method, the extracted BOLD signals is used to estimate BFN and, in turn, identify brain disorders, including mild cognitive impairment (MCI) and autistic spectrum disorder (ASD). Experimental results demonstrate that our proposed TMCCA can lead to better performance than traditional methods.

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10. Wood H, Rusbridge S, Lei J, Lomax C, Elliston J, Russell A. Exploring the Cognitive Model of Social Anxiety in Autistic Young People-The Central Role of Bodily Symptoms. Journal of autism and developmental disorders. 2021.

We explored the role of negative performance beliefs and self-focused attention considered central to psychological models of social anxiety but not studied in autism. Firstly, we compared self- and observer ratings of performance on a social task for 71 young autistic people, 41 high and 30 low in social anxiety, finding a significant main effect of social anxiety but not rater. Subsequently, 76 autistic young people, 46 high and 30 low social anxiety completed measures of interoceptive sensibility and focus of attention following a social task. Only heightened interoceptive sensibility fully mediated the relationship between self-ratings of social performance and social anxiety. These findings suggest awareness of bodily sensations are critical to anxiety in social situations with implications for treatment.

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