1. Alamri ES. {{Efficacy of gluten- and casein-free diets on autism spectrum disorders in children}}. {Saudi medical journal}. 2020; 41(10): 1041-6.
Food containing gluten and casein could play a role in autism spectrum disorders (ASD) symptoms. The present review aimed to update the evidence about the role of the gluten- and casein-free diet (GCFD) on the management of ASD. Web of Science, Science Direct, Google Scholar, and PubMed databases were used to search for randomized controlled trials (RCT) conducted between January 2000 and February 2020. In total, 9 RCT were included (521 participants) with age range between 2 to 18 years. Four of these studies did not show a significant improvement regarding the symptoms of ASD. The rest of these studies (n=5) showed improvement in communication, stereotyped movements, aggressiveness, language, hyperactivity, tantrums, and signs of attention deficit hyperactivity disorder compared to control group. Hence, the data remains insu cient to support the use of GCFD to improve the symptoms of ASD in children.
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2. Al-Jadiri A, Tybor DJ, Mulé C, Sakai C. {{Factors Associated with Resilience in Families of Children with Autism Spectrum Disorder}}. {J Dev Behav Pediatr}. 2020.
OBJECTIVES: Families of children with autism spectrum disorder (ASD) report high levels of stress and poor psychological functioning. Resilience serves to buffer these challenges. Little is known about the factors associated with resilience in these families. METHODS: Data from the National Survey of Children’s Health (NSCH) 2016 were used to investigate independent child, parent, and health care factors associated with resilience in families of children with ASD. We used the NSCH’s family resilience composite derived from 4 survey questions focused on (1) communication, (2) working together to solve problems, (3) drawing on strengths, and (4) staying hopeful during difficult times. We defined family resilience as high or low based on the number of questions answered « all of the time » or « most of the time » versus « some of the time » or « none, » respectively. Using survey weights, univariate and multivariate logistic regression analyses identified associations of child, parent, and health care factors with low family resilience. RESULTS: We analyzed data representing 1151 children with ASD. Low resilience was reported in 32% of families. Low family resilience was significantly associated with parent factors such as not having someone to turn to for support, cutting work hours, and feeling « child hard to care for »; child ASD-related factors such as moderate ASD severity; and health care factors such as lack of satisfaction in communications with providers. CONCLUSION: The findings highlight specific vulnerabilities in families of children with ASD that are associated with low family resilience. Intervention approaches that have the ability to improve overall family resilience should be carefully considered.
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3. Bokadia H, Rai R, Torres EB. {{Digitized Autism Observation Diagnostic Schedule: Social Interactions beyond the Limits of the Naked Eye}}. {Journal of personalized medicine}. 2020; 10(4).
The complexity and non-linear dynamics of socio-motor phenomena underlying social interactions are often missed by observation methods that attempt to capture, describe, and rate the exchange in real time. Unknowingly to the rater, socio-motor behaviors of a dyad exert mutual influence over each other through subliminal mirroring and shared cohesiveness that escape the naked eye. Implicit in these ratings nonetheless is the assumption that the other participant of the social dyad has an identical nervous system as that of the interlocutor, and that sensory-motor information is processed similarly by both agents’ brains. What happens when this is not the case? We here use the Autism Diagnostic Observation Schedule (ADOS) to formally study social dyadic interactions, at the macro- and micro-level of behaviors, by combining observation with digital data from wearables. We find that integrating subjective and objective data reveals fundamentally new ways to improve standard clinical tools, even to differentiate females from males using the digital version of the test. More generally, this work offers a way to turn a traditional, gold-standard clinical instrument into an objective outcome measure of human social behaviors and treatment effectiveness.
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4. Byrne G, Longphuirt EN. {{The psychological impact of quarantine on children with autism spectrum disorder}}. {Irish journal of psychological medicine}. 2020: 1-4.
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5. Chen S, Wang J, Cicek E, Roeder K, Yu H, Devlin B. {{De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types}}. {Mol Autism}. 2020; 11(1): 76.
BACKGROUND: Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses. METHODS: Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein-protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an « ASD disrupted network. » Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner. RESULTS: Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types-excitatory, inhibitory, and neural progenitor-we implicate several hundred genes in risk (FDR [Formula: see text]0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system. LIMITATIONS: Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional. CONCLUSIONS: Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD.
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6. Fu C, Armstrong D, Marsh E, Lieberman D, Motil K, Witt R, Standridge S, Lane J, Dinkel T, Jones M, Hale K, Suter B, Glaze D, Neul J, Percy A, Benke T. {{Multisystem comorbidities in classic Rett syndrome: a scoping review}}. {BMJ paediatrics open}. 2020; 4(1): e000731.
BACKGROUND: Rett syndrome (RTT) is a severe, progressive neurodevelopmental disorder with multisystem comorbidities that evolve across a patient’s lifespan requiring attentive coordination of subspecialty care by primary care providers. A comprehensive, up-to-date synthesis of medical comorbidities in RTT would aid care coordination and anticipatory guidance efforts by healthcare providers. Our objective was to review and summarise published evidence regarding prevalence of RTT medical comorbidities across all relevant organ systems. METHODS: Search of PubMed from January 2000 to July 2019 was performed using the search terms (Rett and MECP2 AND patient) OR (Rett and MECP2 AND cohort). Articles reporting the prevalence of clinical findings in RTT were assessed with respect to the size and nature of the cohorts interrogated and their relevance to clinical care. RESULTS: After review of over 800 records, the multisystem comorbidities of RTT were summarised quantitatively from 18 records comprising both retrospective and prospective cohorts (31-983 subjects). Neurological comorbidities had the highest prevalence, occurring in nearly all individuals with gastrointestinal and orthopaedic concerns almost as prevalent as neurological. With the exception of low bone mineral content which was relatively common, endocrine comorbidities were seen in only around one-third of patients. Although more prevalent compared with the general population, cardiac conduction abnormalities were the least common comorbidity in RTT. CONCLUSIONS: Effective care coordination for RTT requires knowledge of and attention to multiple comorbidities across multiple unrelated organ systems. Many issues common to RTT can potentially be managed by a primary care provider but the need for sub-specialist referral can be anticipated. Since the median life expectancy extends into the sixth decade with evolving subspecialty requirements throughout this time, paediatric providers may be tasked with continued coordination of these comorbidities or transitioning to adult medicine and specialists with experience managing individuals with complex medical needs.
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7. Goris J, Silvetti M, Verguts T, Wiersema JR, Brass M, Braem S. {{Autistic traits are related to worse performance in a volatile reward learning task despite adaptive learning rates}}. {Autism}. 2020: 1362361320962237.
Recent theories propose that autism is characterized by an impairment in determining when to learn and when not. Here, we investigated this hypothesis by estimating learning rates (i.e. the speed with which one learns) in three different environments that differed in rule stability and uncertainty. We found that neurotypical participants with more autistic traits performed worse in a volatile environment (with unstable rules), as they chose less often for the most rewarding option. Exploratory analyses indicated that performance was specifically worse when reward rules were opposite to those initially learned for participants with more autistic traits. However, there were no differences in the adjustment of learning rates between participants with more versus less autistic traits. Together, these results suggest that performance in volatile environments is lower in participants with more autistic traits, but that this performance difference cannot be unambiguously explained by an impairment in adjusting learning rates.
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8. Haegele JA, Zhu X, Bennett HJ. {{Brief Report: Reactivity to Accelerometer Measurement among Adolescents with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2020.
The purpose of this study was to examine reactivity to accelerometer measurement among adolescents with autism spectrum disorder (ASD). A sample of 23 adolescents with ASD (aged 15.00 ± 1.57 years old; 17 boys) wore triaxial accelerometers for at least 8 h per day for seven consecutive days. Descriptive statistics, including arithmetic means and standard deviations, as well as analysis of covariances with repeated measures (ANCOVAs) were conducted, controlling for participant body mass index and gender. While differences were not statistically significant, they exceed reactivity-based recommendations and have implications for future research with adolescents with ASD. The inverse reactivity pattern among adolescents with ASD is a unique finding that has important implications for research in this area.
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9. Janšáková K, Hill M, Čelárová D, Celušáková H, Repiská G, Bičíková M, Máčová L, Ostatníková D. {{Alteration of the steroidogenesis in boys with autism spectrum disorders}}. {Translational psychiatry}. 2020; 10(1): 340.
The etiology of autism spectrum disorders (ASD) remains unknown, but associations between prenatal hormonal changes and ASD risk were found. The consequences of these changes on the steroidogenesis during a postnatal development are not yet well known. The aim of this study was to analyze the steroid metabolic pathway in prepubertal ASD and neurotypical boys. Plasma samples were collected from 62 prepubertal ASD boys and 24 age and sex-matched controls (CTRL). Eighty-two biomarkers of steroidogenesis were detected using gas-chromatography tandem-mass spectrometry. We observed changes across the whole alternative backdoor pathway of androgens synthesis toward lower level in ASD group. Our data indicate suppressed production of pregnenolone sulfate at augmented activities of CYP17A1 and SULT2A1 and reduced HSD3B2 activity in ASD group which is partly consistent with the results reported in older children, in whom the adrenal zona reticularis significantly influences the steroid levels. Furthermore, we detected the suppressed activity of CYP7B1 enzyme readily metabolizing the precursors of sex hormones on one hand but increased anti-glucocorticoid effect of 7α-hydroxy-DHEA via competition with cortisone for HSD11B1 on the other. The multivariate model found significant correlations between behavioral indices and circulating steroids. From dependent variables, the best correlation was found for the social interaction (28.5%). Observed changes give a space for their utilization as biomarkers while reveal the etiopathogenesis of ASD. The aforementioned data indicate a direction of the future research with a focus on the expression and functioning of genes associated with important steroidogenic enzymes in ASD patients from early childhood to adrenarche.
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10. Jassi A, Fernández de la Cruz L, Russell A, Krebs G. {{An Evaluation of a New Autism-Adapted Cognitive Behaviour Therapy Manual for Adolescents with Obsessive-Compulsive Disorder}}. {Child Psychiatry Hum Dev}. 2020.
Obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) frequently co-occur. Standard cognitive behaviour therapy (CBT) for OCD outcomes are poorer in young people with ASD, compared to those without. The aim of this naturalistic study was to evaluate the effectiveness of a novel adolescent autism-adapted CBT manual for OCD in a specialist clinical setting. Additionally, we examined whether treatment gains were maintained at 3-month follow-up. Thirty-four adolescents underwent CBT; at the end of treatment, 51.51% were treatment responders and 21.21% were in remission. At 3-month follow-up, 52.94% were responders and 35.29% remitters. Significant improvements were also observed on a range of secondary measures, including family accommodation and global functioning. This study indicates this adapted package of CBT is associated with significant improvements in OCD outcomes, with superior outcomes to those reported in previous studies. Further investigation of the generalizability of these results, as well as dissemination to different settings, is warranted.
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11. Kamand M, Ilieva M, Forsberg SL, Thomassen M, Svenningsen Å F, Meyer M, Michel TM. {{Generation of autism spectrum disorder patient-derived iPSC line SDUKIi004-A}}. {Stem cell research}. 2020; 49: 102038.
Autism is a heterogeneous neurodevelopmental disorder defined by deficits in socialization, communication, and patterns of behavior. Using stem cells to model brain disordersmay yield new understanding about the underlying neuropathological processes and could prove essential for drug development. We present here a newhuman inducedpluripotentstem cell (iPSC) line (SDUKIi004-A) generated from skin fibroblasts derived from a 21-year old male patient diagnosed with Pervasive DevelopmentalDisorder-Not Otherwise Specified (PDD-NOS)(« FYNEN-cohort »). Reprogramming of the fibroblasts was accomplished using integration-free episomal plasmids. Characterization validated the expression of pluripotency markers, differentiation into the three germ layers, and absence of chromosomal abnormalities.
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12. Martin CA, Sciberras E, Papadopoulos N, Engel L, Hiscock H, Williams K, Howlin P, McGillivray J, Rinehart NJ. {{Associations Between Child Sleep Problem Severity and Maternal Well-Being in Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2020.
This study investigated whether sleep problem severity in children with autism spectrum disorder was associated with maternal well-being. Mothers of 234 children reported on their mental health (Kessler Psychological Distress Scale), parenting stress (Parenting Stress Index-4-SF), health-related quality of life (HRQoL; Assessment of Quality of Life-4D) and their child’s sleep (Children’s Sleep Habits Questionnaire-ASD). Analyses revealed sleep initiation and duration problem severity scores were associated with increased mental health difficulties. Specific child sleep problems were not associated with parenting stress or HRQoL. This study revealed the importance of considering sleep and the family system when assessing maternal well-being. Future research considering parent, child and family factors will be important to informing a family focused approach to mental health.
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13. Oakley BF, Tillmann J, Ahmad J, Crawley D, San José Cáceres A, Holt R, Charman T, Banaschewski T, Buitelaar J, Simonoff E, Murphy D, Loth E. {{How do core autism traits and associated symptoms relate to quality of life? Findings from the Longitudinal European Autism Project}}. {Autism}. 2020: 1362361320959959.
Previous studies suggest that some autistic individuals report lower satisfaction, or well-being, with different aspects of everyday life than those without autism. It is unclear whether this might be partly explained by symptoms of anxiety and/or depression, which affect at least 20%-50% of autistic people. In this study, we measured individual differences in well-being in 573 six to thirty-year-olds with and without a diagnosis of autism. We investigated whether individual differences in well-being were explained by autism traits (e.g. social-communication difficulties) and/or anxiety and depression symptoms. We showed that, though well-being was lower for some autistic individuals, compared to those without autism, many autistic individuals reported good well-being. Where well-being was reduced, this was particularly explained by depression symptoms, across all ages. For children/adolescents, anxiety and social-communication difficulties were also related to some aspects of well-being. Our study suggests that support and services for improving mental health, especially depression symptoms, may also improve broader outcomes for autistic people.
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14. Oakley BFM, Jones EJH, Crawley D, Charman T, Buitelaar J, Tillmann J, Murphy DG, Loth E. {{Alexithymia in autism: cross-sectional and longitudinal associations with social-communication difficulties, anxiety and depression symptoms}}. {Psychological medicine}. 2020: 1-13.
BACKGROUND: Alexithymia (difficulties in identifying and describing emotion) is a transdiagnostic trait implicated in social-emotional and mental health problems in the general population. Many autistic individuals experience significant social-communication difficulties and elevated anxiety/depression and alexithymia. Nevertheless, the role of alexithymia in explaining individual variability in the quality/severity of social-communication difficulties and/or anxiety and depression symptoms in autism remains poorly understood. METHODS: In total, 337 adolescents and adults (autism N = 179) were assessed for alexithymia on the Toronto Alexithymia Scale and for social-communication difficulties, anxiety and depression symptoms. A total of 135 individuals (autism N = 76) were followed up 12-24 months later. We used regression models to establish cross-sectional and longitudinal associations between alexithymia, social-communication difficulties, anxiety and depression symptoms. RESULTS: Autistic individuals reported significantly higher alexithymia than comparison individuals (p < 0.001, r effect size = 0.48), with 47.3% of autistic females and 21.0% of autistic males meeting cut-off for clinically relevant alexithymia (score ⩾61). Difficulties in describing feelings were particularly associated with current self-reported social-communication difficulties [p < 0.001, β = 0.57, 95% confidence interval (CI) 0.44-0.67] and predicted later social-communication difficulties (p = 0.02, β = 0.43, 95% CI 0.07-0.82). Difficulties in identifying feelings were particularly associated with current anxiety symptom severity (p < 0.001, β = 0.54, 95% CI 0.41-0.77) and predicted later anxiety (p = 0.01; β = 0.31, 95% CI 0.08-0.62). CONCLUSIONS: Our findings suggest that difficulties in identifying v. describing emotion are associated with differential clinical outcomes in autism. Psychological therapies targeting emotional awareness may improve social-communication and anxiety symptoms in autism, potentially conferring long-term benefits. Lien vers le texte intégral (Open Access ou abonnement)
15. Olson L, Kinnear M, Chen B, Reynolds S, Ibarra C, Wang T, Linke A, Fishman I. {{Socioeconomic Factors Account for Variability in Language Skills in Preschoolers with Autism Spectrum Disorders}}. {J Dev Behav Pediatr}. 2020.
OBJECTIVE: Although no longer required for a diagnosis, language delays are extremely common in children diagnosed with autism spectrum disorders (ASD). Factors associated with socioeconomic status (SES) have broad-reaching impact on language development in early childhood. Despite recent advances in characterizing autism in early childhood, the relationship between SES and language development in ASD has not received much attention. THE OBJECTIVE OF THIS STUDY WAS: to examine whether toddlers and preschoolers with ASD from low-resource families are more likely to experience language delays above and beyond those associated with autism itself. METHODS: Developmental and diagnostic assessments including the Mullen Scales of Early Learning, the Autism Diagnostic Observation Schedule, Second Edition, and the Vineland Adaptive Behavior Scales were obtained from 62 young children with ASD and 45 typically developing children aged 15 to 64 months. Sociodemographic information including household income, maternal education, and racial/ethnic identity was obtained from caregivers. Multiple regression models were used to test for associations between socioeconomic indices and language scores. RESULTS: Maternal education accounted for variability in expressive language (EL) and receptive language (RL), with lower SES indices associated with lower language skills, and more so in children with ASD. CONCLUSION: These results demonstrate that variability in EL and RL skills in young children with autism can be accounted for by socioeconomic variables. These findings highlight the necessity for targeted intervention and effective implementation strategies for children with ASD from low-resource households and communities and for policies designed to improve learning opportunities and access to services for these young children and their families.
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16. Qureshi F, Adams J, Hanagan K, Kang DW, Krajmalnik-Brown R, Hahn J. {{Multivariate Analysis of Fecal Metabolites from Children with Autism Spectrum Disorder and Gastrointestinal Symptoms before and after Microbiota Transfer Therapy}}. {Journal of personalized medicine}. 2020; 10(4).
Fecal microbiota transplant (FMT) holds significant promise for patients with Autism Spectrum Disorder (ASD) and gastrointestinal (GI) symptoms. Prior work has demonstrated that plasma metabolite profiles of children with ASD become more similar to those of their typically developing (TD) peers following this treatment. This work measures the concentration of 669 biochemical compounds in feces of a cohort of 18 ASD and 20 TD children using ultrahigh performance liquid chromatography-tandem mass spectroscopy. Subsequent measurements were taken from the ASD cohort over the course of 10-week Microbiota Transfer Therapy (MTT) and 8 weeks after completion of this treatment. Univariate and multivariate statistical analysis techniques were used to characterize differences in metabolites before, during, and after treatment. Using Fisher Discriminant Analysis (FDA), it was possible to attain multivariate metabolite models capable of achieving a sensitivity of 94% and a specificity of 95% after cross-validation. Observations made following MTT indicate that the fecal metabolite profiles become more like those of the TD cohort. There was an 82-88% decrease in the median difference of the ASD and TD group for the panel metabolites, and among the top fifty most discriminating individual metabolites, 96% report more comparable values following treatment. Thus, these findings are similar, although less pronounced, as those determined using plasma metabolites.
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17. Schenkelberg MA, Brown WH, McIver KL, Pate RR. {{An observation system to assess physical activity of children with developmental disabilities and delays in preschool}}. {Disability and health journal}. 2020: 101008.
BACKGROUND: Physical activity (PA) behaviors during preschool settings can influence the health and development of children with developmental disabilities (DD). There is a need for a direct observation system that simultaneously assesses PA and preschool environmental contexts. OBJECTIVE: The purpose of this study was to develop an observation instrument for measuring PA and related contextual factors of preschoolers with DD, and to establish content validity and reliability. METHODS: Content validity was established through consultation with experts, informal observations in inclusive and special education preschools, and literature reviews. Categories and codes were identified and modified from existing observational systems for young children. Reliability was assessed in a convenience sample of preschool children with DD using a cross-sectional design. Data were collected using a momentary time sampling system (5-sec observe, 25-sec record) following a focal child. Inter-rater reliability was assessed during 20% of the observation sessions. RESULTS: The instrument development process resulted in ten coding categories that accounted for PA levels, types, and social and physical environmental contexts relevant to preschoolers with disabilities. Observers completed 137.5 observation sessions, yielding 5498 30-s observation intervals. Interval-by-interval percent agreement was excellent (91%-100%) and kappa values were high (0.82-0.99). CONCLUSIONS: The instrument was found to be a reliable measure of PA of preschoolers with DD and provided important contextual information about PA behaviors in early childhood special education settings. Additionally, it allowed for the simultaneous measurement of specific types and contexts of PA behaviors of preschoolers with DD and will be useful for describing PA and informing future interventions.
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18. Soh CP, Goh TJ, Magiati I, Sung M. {{Caregiver- and Child-Reported Anxiety Using an Autism-Specific Measure: Measurement Properties and Correlates of the Anxiety Scale for Children with Autism Spectrum Disorder (ASC-ASD) in Verbal Young People with ASD}}. {J Autism Dev Disord}. 2020.
Identifying and measuring anxiety in young people on the autism spectrum can be challenging. The present study investigated the use of the Anxiety Scale for Children with Autism Spectrum Disorder (ASC-ASD), a self- and caregiver-rated screening tool in a Singaporean sample of ninety-one verbal autistic youths and their caregivers. Internal consistency ranged from satisfactory to desirable (α = .74-.92). Convergent validity with medium-large effect size was established using a structured diagnostic interview, the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID). ASC-ASD scores were positively associated with autistic symptoms and response patterns indicated strong endorsement of autism-specific items. The findings are discussed in relation to existing literature on assessment of anxiety in ASD and in light of the study’s strengths and limitations.
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19. Suzuki T, Miyaki K, Tsutsumi A. {{Which autistic traits are related to depressive symptoms in Japanese workers?}}. {Industrial health}. 2020; 58(5): 414-22.
Individuals with autism spectrum disorders are at a high risk of experiencing depressive symptoms. However, the relationship between autistic traits and depressive symptoms is unclear. This study aimed to identify which autistic traits are related to depressive symptoms in Japanese workers. The study participants included 2,049 workers from all areas of Japan. Autistic traits and depressive symptoms were measured using an abridged Japanese version of the Autism-Spectrum Quotient (AQ-Short) and the Japanese version of the K6 scale, respectively. The AQ-Short comprises five autistic trait subcomponents that assess fascination for numbers/patterns, difficulties with imagination, preference for routine, difficulties with social skills, and attention-switching difficulties. Linear regression analyses were performed to estimate the association between total and subcomponent autistic trait scores and depressive symptoms. Participants with higher total autistic trait scores were significantly more likely to have depressive symptoms (p<0.001). When scores on the five autistic trait subcomponents were entered simultaneously into the model, participants with higher scores on all subcomponents other than 'difficulties with imagination' were significantly more likely to report depressive symptoms. Total autistic traits and autistic trait subcomponents could be used for early detection of the risk of depressive symptoms. Lien vers le texte intégral (Open Access ou abonnement)
20. Wang L, Zhang Y, Li K, Wang Z, Wang X, Li B, Zhao G, Fang Z, Ling Z, Luo T, Xia L, Li Y, Guo H, Hu Z, Li J, Sun Z, Xia K. {{Functional relationships between recessive inherited genes and genes with de novo variants in autism spectrum disorder}}. {Mol Autism}. 2020; 11(1): 75.
BACKGROUND: Both de novo variants and recessive inherited variants were associated with autism spectrum disorder (ASD). This study aimed to use exome data to prioritize recessive inherited genes (RIGs) with biallelically inherited variants in autosomes or X-linked inherited variants in males and investigate the functional relationships between RIGs and genes with de novo variants (DNGs). METHODS: We used a bioinformatics pipeline to analyze whole-exome sequencing data from 1799 ASD quads (containing one proband, one unaffected sibling, and their parents) from the Simons Simplex Collection and prioritize candidate RIGs with rare biallelically inherited variants in autosomes or X-linked inherited variants in males. The relationships between RIGs and DNGs were characterized based on different genetic perspectives, including genetic variants, functional networks, and brain expression patterns. RESULTS: Among the biallelically or hemizygous constrained genes that were expressed in the brain, ASD probands carried significantly more biallelically inherited protein-truncating variants (PTVs) in autosomes (p = 0.038) and X-linked inherited PTVs in males (p = 0.026) than those in unaffected siblings. We prioritized eight autosomal, and 13 X-linked candidate RIGs, including 11 genes already associated with neurodevelopmental disorders. In total, we detected biallelically inherited variants or X-linked inherited variants of these 21 candidate RIGs in 26 (1.4%) of 1799 probands. We then integrated previously reported known or candidate genes in ASD, ultimately obtaining 70 RIGs and 87 DNGs for analysis. We found that RIGs were less likely to carry multiple recessive inherited variants than DNGs were to carry multiple de novo variants. Additionally, RIGs and DNGs were significantly co-expressed and interacted with each other, forming a network enriched in known functional ASD clusters, although RIGs were less likely to be enriched in these functional clusters compared with DNGs. Furthermore, although RIGs and DNGs presented comparable expression patterns in the human brain, RIGs were less likely to be associated with prenatal brain regions, the middle cortical layers, and excitatory neurons than DNGs. LIMITATIONS: The RIGs analyzed in this study require functional validation, and the results should be replicated in more patients with ASD. CONCLUSIONS: ASD RIGs were functionally associated with DNGs; however, they exhibited higher heterogeneity than DNGs.
