1. Birnbaum R, Mahjani B, Loos RJF, Sharp AJ. Clinical Characterization of Copy Number Variants Associated With Neurodevelopmental Disorders in a Large-scale Multiancestry Biobank. JAMA psychiatry. 2022; 79(3): 250-9.

IMPORTANCE: Past studies identified rare copy number variants (CNVs) as risk factors for neurodevelopmental disorders (NDDs), including autism spectrum disorder and schizophrenia. However, the clinical characterization of NDD CNVs is understudied in population cohorts unselected for neuropsychiatric disorders and in cohorts of diverse ancestry. OBJECTIVE: To identify individuals harboring NDD CNVs in a multiancestry biobank and to query their enrichment for select neuropsychiatric disorders as well as association with multiple medical disorders. DESIGN, SETTINGS, AND PARTICIPANTS: In a series of phenotypic enrichment and association analyses, NDD CNVs were clinically characterized among 24 877 participants in the BioMe biobank, an electronic health record-linked biobank derived from the Mount Sinai Health System, New York, New York. Participants were recruited into the biobank since September 2007 across diverse ancestry and medical and neuropsychiatric specialties. For the current analyses, electronic health record data were analyzed from May 2004 through May 2019. MAIN OUTCOMES AND MEASURES: NDD CNVs were identified using a consensus of 2 CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by novel in-silico clinical assessments. RESULTS: Of 24 877 participants, 14 586 (58.7%) were female; self-reported ancestry categories included 5965 (24.0%) who were of African ancestry, 7892 (31.7%) who were of European ancestry, and 8536 (34.3%) who were of Hispanic ancestry; and the mean (SD) age was 50.5 (17.3) years. Among 24 877 individuals, the prevalence of 64 NDD CNVs was 2.5% (n = 627), with prevalence varying by locus, corroborating the presence of some relatively highly prevalent NDD CNVs (eg, 15q11.2 deletion/duplication). An aggregate set of NDD CNVs were enriched for congenital disorders (odds ratio, 2.0; 95% CI, 1.1-3.5; P = .01) and major depressive disorder (odds ratio, 1.5; 95% CI, 1.1-2.0; P = .01). In a meta-analysis of medical diagnoses (n = 195 hierarchically clustered diagnostic codes), NDD CNVs were significantly associated with several medical outcomes, including essential hypertension (z score = 3.6; P = 2.8 × 10-4), kidney failure (z score = 3.3; P = 1.1 × 10-3), and obstructive sleep apnea (z score = 3.4; P = 8.1 × 10-4) and, in another analysis, morbid obesity (z score = 3.8; P = 1.3 × 10-4). Further, NDD CNVs were associated with increased body mass index in a multiancestry analysis (β = 0.19; 95% CI, 0.10-0.31; P = .003). For 36 common serum tests, there was no association with NDD CNVs. CONCLUSIONS AND RELEVANCE: Clinical features of individuals harboring NDD CNVs were elucidated in a large-scale, multiancestry biobank, identifying enrichments for congenital disorders and major depressive disorder as well as associations with several medical outcomes, including hypertension, kidney failure, and obesity and obesity-related phenotypes, specifically obstructive sleep apnea and increased body mass index. The association between NDD CNVs and obesity outcomes indicate further potential pleiotropy of NDD CNVs beyond neurodevelopmental outcomes previously reported. Future clinical genetic investigations may lead to insights of at-risk individuals and therapeutic strategies targeting specific genetic variants. The importance of diverse inclusion within biobanks and considering the effect of rare genetic variants in a multiancestry context is evident.

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2. Chan DV, Doran JD, Galobardi OD. Beyond Friendship: The Spectrum of Social Participation of Autistic Adults. Journal of autism and developmental disorders. 2022: 1-14.

Difficulties with social interactions and communication that characterize autism persist in adulthood. While social participation in adulthood is often marked by social isolation and limited close friendships, this qualitative study describes the range of social participation activities and community contacts, from acquaintances to close relationships, that contributed to connection from the perspective of 40 autistic adults. Qualitative data from interviews around social and community involvement were analyzed and revealed five main contexts where social participation occurred: vocational contexts, neighborhoods, common interest groups, support services and inclusive environments, and online networks and apps. Implications for practice to support a range of social participation include engaging in newer social networking avenues, as well as traditional paths through employment and support services.

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3. Dekker L, Hooijman L, Louwerse A, Visser K, Bastiaansen D, Ten Hoopen L, De Nijs P, Dieleman G, Ester W, Van Rijen S, Truijens F, Van der Hallen R. Impact of the COVID-19 pandemic on children and adolescents with autism spectrum disorder and their families: a mixed-methods study protocol. BMJ open. 2022; 12(1): e049336.

BACKGROUND: The COVID-19 pandemic is a challenge for everyone, particularly for children and adolescents with autism spectrum disorder (ASD). ASD is a developmental disorder characterised by limitations in social communication, repetitive behavioural patterns, and limited interests, and activities. It is expected that many families with children with ASD will experience more problems due to the COVID-19 pandemic and the related public health restrictions. At the same time, some may experience improved functioning, due to fewer expectations and social demands. METHODS/DESIGN: In a mixed-method study to identify the impact of the COVID-19 pandemic, parents of children with ASD (ages 4-21) who were in care pre-COVID-19 at one of three large mental healthcare institutions in the region of Rotterdam participated (68 for T0, 57 for T1). The aims are (1) to investigate the impact of the COVID-19 pandemic on overall functioning and autistic symptoms of the child/adolescent with ASD, as well as parental and family functioning (QUANT-QUAL), in both the short term and longer term, and (2) to investigate risk and protective factors (in light of resilience) (QUANT-qual) and (3) to investigate care and informational needs (QUAL-quant). Pre-COVID-19 baseline data will be retrieved from clinical records. Participants will fill out two surveys (one during a COVID-19 peak-January-May 2021-and one thereafter). Survey participants were invited to participate in interviews (n=27). Surveys include measures thar were included pre-COVID-19 (ie, overall functioning and autism symptoms) as well as specific measures to identify family functioning and COVID-19 impact. The semistructured interviews focus on child, parent and family functioning and care-and informational needs. ETHICS AND DISSEMINATION: The Medical Ethics Committee of the Erasmus MC has approved the study. Findings will be available to families of children with ASD, their care providers, the funders, autism societies, the government and other researchers.

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4. Erden S, Nalbant K, Kılınç İ. Investigation of Relaxin-3 Serum Levels in terms of Social Interaction, Communication, and Appetite as a Biomarker in Children with Autism. Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology. 2022; 20(1): 135-42.

OBJECTIVE: To investigate the possible relationship between relaxin-3 and autism spectrum disorder (ASD). METHODS: Serum relaxin-3 was measured in 80 children (50 children diagnosed with ASD and 30 controls). Symptom severity in the ASD group was evaluated by the Childhood Autism Rating Scale (CARS). Behavioral and nutritional problems in the groups were evaluated using the Abnormal Behavior Checklist (ABC) and the Children’s Eating Behavior Questionnaire (CEBQ). RESULTS: Our findings showed that serum relaxin-3 levels were higher in children with ASD than in the controls. The listening response sub-scale score of the CARS scale was found to decrease as the level of relaxin-3 increased. However, as relaxin-3 levels increased in children with ASD, it was found that the speech problem sub-scale score on the ABC scale and the desire to drink score on the CEBQ scale increased, but the satiety responsiveness and food fussiness scores decreased. CONCLUSION: This study the first to investigate serum levels of relaxin-3, which has a role in regulating social behavior and nutritional behavior in children with ASD.

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5. Feng X, Jiang Q, Zhang Y, Li T, Wei W, Yu J, Li W, Li J. Pediatric Tuina in children with autism spectrum disorder: a study protocol for a randomized controlled trial. Trials. 2022; 23(1): 75.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by repetitive stereotypical behavior and communication deficits. Currently, it lacks a specific clinical treatment method. Pediatric Tuina is a recent therapy in traditional Chinese medicine (TCM) and has been used to treat children with ASD. Nonetheless, it remains uncommon given the lack of large-scale evidence-based medical studies. This study aims to compare the efficacy of Tuina and conventional treatment in children with ASD. METHODS: Eligible children will be randomly assigned to either the pediatric Tuina plus conventional treatment group or to the conventional treatment alone group based on a random table at a ratio of 1:1. The effectiveness of the Tuina intervention for ASD will be evaluated by a third-party organization. The pre- and post-intervention scores on the Childhood Autism Rating Scale comprised the primary outcome, whereas pre- and post-intervention scores on the Autism Treatment Evaluation Checklist were the secondary outcomes to assess improvement in symptoms. Baseline values of the participants will be determined at the time of registration. Outcomes will be evaluated after the 30th treatment session. The follow-up period will last for 6 months after treatment. DISCUSSION: This study will evaluate the effectiveness and safety of Tuina in the treatment of ASD. The results of this study could provide reliable evidence to improve the management of patients with ASD. TRIAL REGISTRATION: Chinese Clinical Trial Registry (CHICTR), ChiCTR2000040452 . Registered on 28 November 2020.

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6. Ghanouni P, Quirke S. Resilience and Coping Strategies in Adults with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2022: 1-12.

Individuals with Autism spectrum disorder (ASD) are prone to stress and anxiety affecting their mental health. Although developing coping and resilience are key to cope with stressors of life, limited research exists. We aimed to explore stakeholders’ experiences related to the coping and resilience of adults with ASD. We interviewed 22 participants, including 13 adults with ASD, five parents, and four service provides of adults with ASD from various Canadian provinces. Using thematic analysis, three themes emerged including: (a) societal expectations and conformity, (b) adjusting daily routines, and (c) learning overtime. This study highlights the importance of coping and informs the development of services to help enhance resilience among adults with ASD.

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7. Kikuchi Y, Akechi H, Senju A, Tojo Y, Osanai H, Saito A, Hasegawa T. Attention to live eye contact in adolescents with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2022; 15(4): 702-11.

A number of studies have reported diminished attention to the eyes in individuals with autism spectrum disorder (ASD). These studies predominantly used static images of faces as stimuli. Recent studies, however, have shown enhanced response to eye contact in typically developing (TD) individuals when they observe a person in a live interaction. We investigated physiological orienting to perceived eye contact in adolescents with ASD and TD adolescents when they observed a person in live interaction or viewed a photograph of the same person’s face. We measured heart rate (HR) deceleration as an index of attentional orienting. Adolescents with ASD, as well as TD adolescents, showed significant HR deceleration for the direct gaze compared to an averted gaze in the live condition, but not in the photographic condition. The results suggest an intact response to perceived eye contact in individuals with ASD during a live face-to-face interaction. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) have a different eye gaze pattern when observing photographic faces. However, little is known about how individuals with ASD process a real person’s face. We measured heart rate (HR) and found that adolescents with ASD showed the typical decline in HR when they made eye contact with a real person, which suggests that both groups of individuals directed their attention to eye contact in a live face-to-face interaction.

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8. Mouga S, Duarte IC, Café C, Sousa D, Duque F, Oliveira G, Castelo-Branco M. Parahippocampal deactivation and hyperactivation of central executive, saliency and social cognition networks in autism spectrum disorder. Journal of neurodevelopmental disorders. 2022; 14(1): 9.

BACKGROUND: The concomitant role of the Central Executive, the Saliency and the Social Cognition networks in autism spectrum disorder (ASD) in demanding ecological tasks remains unanswered. We addressed this question using a novel task-based fMRI virtual-reality task mimicking a challenging daily-life chore that may present some difficulties to individuals with ASD: the EcoSupermarketX. METHODS: Participants included 29 adolescents: 15 with ASD and 15 with typical neurodevelopment (TD). They performed the EcoSupermarketX (a shopping simulation with three goal-oriented sub-tasks including « no cue », « non-social » or « social » cues), during neuroimaging and eye-tracking. RESULTS: ASD differed from TD only in total time and distance to complete the « social cue » sub-task with matched eye-tracking measures. Neuroimaging revealed simultaneous hyperactivation across social, executive, and saliency circuits in ASD. In contrast, ASD showed reduced activation in the parahippocampal gyrus, involved in scene recognition. CONCLUSIONS: When performing a virtual shopping task matching the performance of controls, ASD adolescents hyperactivate three core networks: executive, saliency and social cognition. Parahippocampal hypoactivation is consistent with effortless eidetic scene processing, in line with the notion of peaks and valleys of neural recruitment in individuals with ASD. These hyperactivation/hypoactivation patterns in daily life tasks provide a circuit-level signature of neural diversity in ASD, a possible intervention target.

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9. Yan Y, Tian M, Li M, Zhou G, Chen Q, Xu M, Hu Y, Luo W, Guo X, Zhang C, Xie H, Wu QF, Xiong W, Liu S, Guan JS. ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder. Neuron. 2022; 110(7): 1156-72.e9.

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l(+/-) mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l(+/-) mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.

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10. Yi Z, Song Z, Li F, Yang C, Xue J, Li L, Zhang M, Zhang Y. A novel de novo frameshift variation in the SON gene causing severe global developmental delay and seizures in a Chinese female. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2022; 82(3): 271-6.

BACKGROUND: With the rapid development of genetic detection technology, especially next-generation sequencing, identification of the aetiology of unexplained intellectual disabilities accompanied by seizures and other dysmorphic features has become possible. The purpose of our paper is to make a definitive diagnosis of a girl with neonatal hypotonia, severe global developmental delay, seizures and mild facial dysmorphism. METHODS: The clinical data of the patient were retrospectively studied. Whole-exome sequencing was performed on a blood sample from the patient. Subsequently, Sanger sequencing was utilized for validation of variants and parental validation. RESULTS: The patient had hypotonia since the neonatal period. She showed a significant delay in physical and psychomotor development. She did not have any speech until the age of 2 years and 6 months. She had seizures that were easy to control with levetiracetam. The craniocerebral magnetic resonance imaging (MRI) then showed mild delayed myelination, enlarged bilateral ventricles and widened frontotemporal extracerebral space. Interictal video electroencephalogram (VEEG) was normal. She had esotropia and mild facial abnormalities with a flat nasal bridge and a short nose. She showed no abnormalities in the heart, genitourinary or skeletal systems. Whole-exome sequencing revealed a novel de novo variant c.5334_5335delAG (p. Arg1778Serfs*11) in the SON gene. CONCLUSION: Our paper reports a novel variant in the SON gene and provides a definitive diagnosis of a female with neonatal hypotonia, severe global developmental delay, seizures and mild facial abnormalities, which are symptoms consistent with Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome).

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