1. Castro CP, Diehl AG, Boyle AP. Challenges in screening for de novo noncoding variants contributing to genetically complex phenotypes. HGG Adv;2023 (Jul 13);4(3):100210.

Understanding the genetic basis for complex, heterogeneous disorders, such as autism spectrum disorder (ASD), is a persistent challenge in human medicine. Owing to their phenotypic complexity, the genetic mechanisms underlying these disorders may be highly variable across individual patients. Furthermore, much of their heritability is unexplained by known regulatory or coding variants. Indeed, there is evidence that much of the causal genetic variation stems from rare and de novo variants arising from ongoing mutation. These variants occur mostly in noncoding regions, likely affecting regulatory processes for genes linked to the phenotype of interest. However, because there is no uniform code for assessing regulatory function, it is difficult to separate these mutations into likely functional and nonfunctional subsets. This makes finding associations between complex diseases and potentially causal de novo single-nucleotide variants (dnSNVs) a difficult task. To date, most published studies have struggled to find any significant associations between dnSNVs from ASD patients and any class of known regulatory elements. We sought to identify the underlying reasons for this and present strategies for overcoming these challenges. We show that, contrary to previous claims, the main reason for failure to find robust statistical enrichments is not only the number of families sampled, but also the quality and relevance to ASD of the annotations used to prioritize dnSNVs, and the reliability of the set of dnSNVs itself. We present a list of recommendations for designing future studies of this sort that will help researchers avoid common pitfalls.

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2. Frackowiak J, Mazur-Kolecka B. Intraneuronal accumulation of amyloid-β peptides as the pathomechanism linking autism and its co-morbidities: epilepsy and self-injurious behavior – the hypothesis. Front Mol Neurosci;2023;16:1160967.

Autism spectrum disorder (ASD) is associated with enhanced processing of amyloid-β precursor protein (APP) by secretase-α, higher blood levels of sAPPα and intraneuronal accumulation of N-terminally truncated Aβ peptides in the brain cortex – mainly in the GABAergic neurons expressing parvalbumin – and subcortical structures. Brain Aβ accumulation has been also described in epilepsy-the frequent ASD co-morbidity. Furthermore, Aβ peptides have been shown to induce electroconvulsive episodes. Enhanced production and altered processing of APP, as well as accumulation of Aβ in the brain are also frequent consequences of traumatic brain injuries which result from self-injurious behaviors, another ASD co-morbidity. We discuss distinct consequences of accumulation of Aβ in the neurons and synapses depending on the Aβ species, their posttranslational modifications, concentration, level of aggregation and oligomerization, as well as brain structures, cell types and subcellular structures where it occurs. The biological effects of Aβ species which are discussed in the context of the pathomechanisms of ASD, epilepsy, and self-injurious behavior include modulation of transcription-both activation and repression; induction of oxidative stress; activation and alteration of membrane receptors’ signaling; formation of calcium channels causing hyper-activation of neurons; reduction of GABAergic signaling – all of which lead to disruption of functions of synapses and neuronal networks. We conclude that ASD, epilepsy, and self-injurious behaviors all contribute to the enhanced production and accumulation of Aβ peptides which in turn cause and enhance dysfunctions of the neuronal networks that manifest as autism clinical symptoms, epilepsy, and self-injurious behaviors.

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3. Goff KM, Liebergall SR, Jiang E, Somarowthu A, Goldberg EM. VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome. Cell Rep;2023 (Jun 12);42(6):112628.

Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocortical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable in DS (Scn1a(+/-)) mice. Here, we investigate VIP-IN function at the circuit and behavioral level by performing in vivo 2-photon calcium imaging in awake wild-type (WT) and Scn1a(+/-) mice. VIP-IN and pyramidal neuron activation during behavioral transition from quiet wakefulness to active running is diminished in Scn1a(+/-) mice, and optogenetic activation of VIP-INs restores pyramidal neuron activity to WT levels during locomotion. VIP-IN selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors in addition to cellular- and circuit-level deficits in VIP-IN function, but without epilepsy, sudden death, or avoidance behaviors seen in the global model. Hence, VIP-INs are impaired in vivo, which may underlie non-seizure cognitive and behavioral comorbidities in DS.

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4. Kaminski VL, Michita RT, Ellwanger JH, Veit TD, Schuch JB, Riesgo RDS, Roman T, Chies JAB. Exploring potential impacts of pregnancy-related maternal immune activation and extracellular vesicles on immune alterations observed in autism spectrum disorder. Heliyon;2023 (May);9(5):e15593.

Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders usually observed in early life, with impacts on behavioral and social skills. Incidence of ASD has been dramatically increasing worldwide, possibly due to increase in awareness/diagnosis as well as to genetic and environmental triggers. Currently, it is estimated that ∼1% of the world population presents ASD symptoms. In addition to its genetic background, environmental and immune-related factors also influence the ASD etiology. In this context, maternal immune activation (MIA) has recently been suggested as a component potentially involved in ASD development. In addition, extracellular vesicles (EVs) are abundant at the maternal-fetal interface and are actively involved in the immunoregulation required for a healthy pregnancy. Considering that alterations in concentration and content of EVs have also been associated with ASD, this article raises a debate about the potential roles of EVs in the processes surrounding MIA. This represents the major differential of the present review compared to other ASD studies. To support the suggested correlations and hypotheses, findings regarding the roles of EVs during pregnancy and potential influences on ASD are discussed, along with a review and update concerning the participation of infections, cytokine unbalances, overweight and obesity, maternal anti-fetal brain antibodies, maternal fever, gestational diabetes, preeclampsia, labor type and microbiota unbalances in MIA and ASD.

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5. Kim YR, Song DY, Bong G, Han JH, Kim JH, Yoo HJ. Clinical characteristics of comorbid tic disorders in autism spectrum disorder: exploratory analysis. Child Adolesc Psychiatry Ment Health;2023 (Jun 12);17(1):71.

BACKGROUND: The frequency, clinical characteristics, and associated symptoms of comorbid tic disorders in individuals with autism spectrum disorder (ASD) remain unclear. METHODS: We included subsets of individuals from a larger genetic study who were diagnosed with ASD (n = 679; age: 4-18 years) and completed the Yale Global Tic Severity Scale (YGTSS) questionnaire. Based on the YGTSS score, the individuals were divided into two groups: ASD only (n = 554) and ASD with tics (n = 125). Individuals were assessed using the verbal and non-verbal intelligence quotient (IQ), Vineland Adaptive Behavior Scale (VABS-2), Social Responsiveness Scale-2 (SRS-2), Child Behavior Checklists (CBCL), and Yale-Brown Obsessive-Compulsive Scale (YBOCS), followed by between-group comparisons. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 26. RESULTS: Tic symptoms were observed in 125 (18.4%) participants; among them, most participants presented both motor and vocal tics (n = 40, 40.0%). The ASD with tics group had a significantly higher average age and full-scale IQ score than the ASD only group. After adjusting for age, the ASD with tics group had significantly higher scores in the SRS-2, CBCL, and YBOCS subdomains than the ASD only group. Furthermore, all variables except the non-verbal IQ and VABS-2 scores were positively correlated with the YGTSS total score. Finally, the proportion of tic symptoms was significantly higher among individuals with a higher IQ score (≥ 70). CONCLUSIONS: The IQ score was positively correlated with the proportion of tic symptoms among individuals with ASD. Moreover, the severity of the core and comorbid symptoms of ASD was associated with the occurrence and severity of tic disorders. Our findings suggest the need for appropriate clinical interventions for individuals with ASD. Trial registration This study retrospectively registered participants.

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6. Kishimoto T, Liu S, Zhang L, Li S. How do autistic severity and family functioning influence parental stress in caregivers of children with autism spectrum disorder in China? The important role of parental self-efficacy. Front Psychol;2023;14:956637.

INTRODUCTION: Parental stress among primary caregivers of children with autism spectrum disorder (ASD) is a significant concern. While previous research indicates that both family and child factors substantially influence parental stress, a few studies have comprehensively examined these factors from family, parent, and child perspectives. Moreover, the psychological mechanisms underlying parental stress remain underexplored. METHOD: This study obtained a valid sample of 478 primary caregivers of children diagnosed with ASD in China and employed mediation and moderated mediation analyses to investigate the relationships between family adaptability and cohesion (FAC), ASD severity, parental self-efficacy, and parental stress. RESULT: Results revealed that higher FAC was linked to reduced parental stress through increased parental self-efficacy. The indirect effect of parental self-efficacy was more substantial for caregivers of children with severe symptoms than those with mild symptoms. DISCUSSION: These findings offer insights into how FAC influences parental stress and underscore the importance of parental self-efficacy as a coping resource for mitigating parental stress. This study provides valuable theoretical and practical implications for understanding and addressing parental stress, particularly in families raising children with ASD.

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7. Li X, Li JC, Lu QQ, Zhang F, Zhang SQ. Research status and prospects of acupuncture for autism spectrum disorders. Front Psychiatry;2023;14:942069.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder and has a predilection for children. Its symptoms, such as lifelong social communication deficits and repetitive sensory-motor behaviors, put a huge burden on the patient’s family and society. Currently, there is no cure for ASD, and some medications that can improve its symptoms are often accompanied by adverse effects. Among many complementary and alternative medicine (CAM) therapies, acupuncture has shown promising application potential, but after years of practice, it has not been recognized as the preferred CAM therapy for ASD. Therefore, we analyzed and discussed the clinical study reports of acupuncture in the treatment of ASD in the past 15 years from the aspects of study subjects, group setting, intervention modalities, acupoint selection, outcome evaluation, and safety. The data accumulated at present are not sufficient to support the clinical effectiveness of acupuncture in ASD and to justify its use in clinical practice. They provide, however, initial evidence of possible effectiveness and encourage further investigation in order to reach firm conclusions. Based on a comprehensive analysis, we believed that following the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) and Consolidated Standards of Reporting Trials (CONSORT), screening the optimal combination of acupoints applying a rigorous scientific study design, and performing the related functional experiments may be the effective way to convincingly test the hypothesis that acupuncture may be beneficial in ASD patients. The significance of this review is to provide a reference for researchers to carry out high-quality clinical trials of acupuncture in the treatment of ASD from the perspective of the combination of modern medicine and traditional Chinese medicine.

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8. Marini S, D’Agostino L, Ciamarra C, Gentile A. Deep brain stimulation for autism spectrum disorder. World J Psychiatry;2023 (May 19);13(5):174-181.

Deep brain stimulation (DBS) is a medical treatment that aims to obtain therapeutic effects by applying chronic electrical impulses in specific brain structures and neurological circuits. Over the years, DBS has been studied for the treatment of many psychiatric disorders. Scientific research on the use of DBS in people with autism has focused this interest mainly on treatment-resistant obsessive-compulsive disorder, drug-resistant epilepsy, self-injurious behaviors (SIB), and aggressive behaviors toward the self. Autism spectrum disorder (ASD) includes a group of developmental disabilities characterized by patterns of delay and deviance in the development of social, communicative, and cognitive skills and the presence of repetitive and stereotyped behaviors as well as restricted interests. People with autism often have numerous medical and psychiatric comorbidities that worsen the quality of life of patients and their caregivers. Obsessive-compulsive symptoms can be found in up to 81.3% of people with autism. They are often severe, refractory to treatment, and particularly difficult to treat. SIB has a high prevalence in severely retarded individuals and is often associated with autism. Drug treatment of both autism and SIB presents a therapeutic challenge. To describe the current state of the art regarding the efficacy of DBS in people with ASD, a literature search was conducted for relevant studies using the PubMed database. Thirteen studies have been considered in this paper. Up to date, DBS has been used for the stimulation of the nucleus accumbens, globus pallidus internus, anterior limb of the internal capsule, ventral anterior limb of the internal capsule, basolateral amygdala, ventral capsule and ventral striatum, medial forebrain bundle, and posterior hypothalamus. In the total sample of 16 patients, 4 were adolescents, and 12 were adults. All patients had symptoms resistant to multiple drug therapy. Many patients taken into consideration by the studies showed clinical improvements as evidenced by the scores of the psychopathological scales used. In some cases, clinical improvements have varied over time, which may require further investigation. Among the new therapeutic perspectives, DBS could be a valid option. However, further, and more in-depth research is needed in this field.

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9. Palmieri M, Pozzer D, Landsberger N. Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives. Front Neurosci;2023;17:1172805.

Loss and gain of functions mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene are responsible for a set of generally severe neurological disorders that can affect both genders. In particular, Mecp2 deficiency is mainly associated with Rett syndrome (RTT) in girls, while duplication of the MECP2 gene leads, mainly in boys, to the MECP2 duplication syndrome (MDS). No cure is currently available for MECP2 related disorders. However, several studies have reported that by re-expressing the wild-type gene is possible to restore defective phenotypes of Mecp2 null animals. This proof of principle endorsed many laboratories to search for novel therapeutic strategies to cure RTT. Besides pharmacological approaches aimed at modulating MeCP2-downstream pathways, genetic targeting of MECP2 or its transcript have been largely proposed. Remarkably, two studies focused on augmentative gene therapy were recently approved for clinical trials. Both use molecular strategies to well-control gene dosage. Notably, the recent development of genome editing technologies has opened an alternative way to specifically target MECP2 without altering its physiological levels. Other attractive approaches exclusively applicable for nonsense mutations are the translational read-through (TR) and t-RNA suppressor therapy. Reactivation of the MECP2 locus on the silent X chromosome represents another valid choice for the disease. In this article, we intend to review the most recent genetic interventions for the treatment of RTT, describing the current state of the art, and the related advantages and concerns. We will also discuss the possible application of other advanced therapies, based on molecular delivery through nanoparticles, already proposed for other neurological disorders but still not tested in RTT.

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10. Persico AM. Commentary: Research status and prospects of acupuncture for autism spectrum disorders. Front Psychiatry;2023;14:1179048.

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11. Riebel M, Rohmer O, Charles E, Lefebvre F, Weibel S, Weiner L. Compassion-focused therapy (CFT) for the reduction of the self-stigma of mental disorders: the COMpassion for Psychiatric disorders, Autism and Self-Stigma (COMPASS) study protocol for a randomized controlled study. Trials;2023 (Jun 12);24(1):393.

BACKGROUND: People with mental disorders face frequent stigmatizing attitudes and behaviors from others. Importantly, they can internalize such negative attitudes and thus self-stigmatize. Self-stigma is involved in diminished coping skills leading to social avoidance and difficulties in adhering to care. Reducing self-stigma and its emotional corollary, shame, is thus crucial to attenuate the negative outcomes associated with mental illness. Compassion-focused therapy (CFT) is a third-wave cognitive behavioral therapy that targets shame reduction and hostile self-to-self relationship and allows for symptom improvement while increasing self-compassion. Although shame is a prominent part of the concept of self-stigma, the efficacy of CFT has never been evaluated in individuals with high levels of self-stigma. The purpose of this study is to evaluate the efficacy and acceptability of a group-based CFT program on self-stigma, compared to a psychoeducation program for self-stigma (Ending Self-Stigma) and to treatment as usual (TAU). We hypothesize that diminished shame and emotional dysregulation and increased self-compassion will mediate the relationship between self-stigma improvements post-therapy in the experimental group. METHODS: This seven-center trial will involve 336 participants diagnosed with a severe mental illness and/or autism spectrum disorder and reporting high levels of self-stigma. Participants will be randomized into one of three treatment arms: 12 week-treatment of compassion-focused therapy (experimental arm), 12 week-treatment of Psychoeducation (active control arm), and TAU (treatment as usual-passive control arm). The primary outcome is the decrease of self-stigma scores on a self-report scale, i.e., ISMI, at 12 weeks. Secondary endpoints include sustainability of self-stigma scores (ISMI) and self-reported scores regarding target psychological dimensions, e.g., shame and emotional regulation, social functioning, and psychiatric symptoms. Assessments are scheduled at pretreatment, post-treatment (at 12 weeks), and at 6-month follow-up. Acceptability will be evaluated via (i) the Credibility and Expectancy Questionnaire at T0, (ii) the Consumer Satisfaction Questionnaire for Psychotherapeutic Services posttreatment and at 6-month follow-up, (iii) attendance, and (iv) dropout rates. DISCUSSION: This study will evaluate the potential efficacy and acceptability of a group-based CFT program on the decrease of self-stigma and thereby contribute to the continuing development of evidence-based therapeutic interventions for the internalized stigma of mental and neurodevelopmental disorders. TRIAL REGISTRATION: ClinicalTrials.gov NCT05698589. Registered on January 26, 2023.

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12. Susko M, Armstrong VL, Brian JA, Bryson SE, Kushki A, Sacrey LR, Zwaigenbaum L, Smith IM. Behavioural reactions to an emotion evoking task in infants at increased likelihood for autism spectrum disorder. Infant Behav Dev;2023 (Jun 10);72:101848.

Infants at increased likelihood for autism spectrum disorder (ASD) exhibit more negative affect and avoidance behaviour than typically developing infants, and children with ASD express fear differently than typically developing peers. We examined behavioural reactions to emotion-evoking stimuli in infants at increased familial likelihood for ASD. Participants included 55 increased likelihood (IL) infants (i.e., siblings of children diagnosed with ASD) and 27 typical likelihood (TL) infants (i.e., no family history of ASD). At 18 months, we showed infants two masks that commonly elicit fearful responses in older children and examined potential behavioural differences in approach, avoidance, ‘freezing’, crying, gaze aversion, and smiling. At 24 months, infants were assessed with the Toddler Module of the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2). Results of video-based coding showed that (1) IL infants exhibited more intense avoidance behaviour than TL infants in response to masks, and (2) intensity of avoidance and duration of freezing were positively correlated with ADOS-2 symptom severity scores. Findings suggest that differences in response to emotion-eliciting stimuli may predict later ASD symptoms. Such behavioural differences may inform early detection and intervention in ASD.

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13. Tekin Ç, Gökçe A, Boz G, Aslan M, Yiğit E. Reasons for parental hesitancy or refusal of childhood vaccination in Türkiye. East Mediterr Health J;2023 (May 31);29(5):343-353.

BACKGROUND: Although vaccines play a critical role in the control of infectious diseases and disease outbreaks, vaccination rates have been declining in recent years because of vaccine hesitancy or refusal. AIMS: We aimed to determine the rates and reasons for parental hesitancy or refusal of vaccination for their children in Türkiye. METHOD: A total of 1100 participants selected from 26 regions of Türkiye were involved in this cross-sectional study conducted between July 2020 and April 2021. Using a questionnaire, we collected data on the sociodemographic characteristics of parents, the status of vaccine hesitancy or refusal for their children, and reasons for the hesitancy or refusal. Using Excel and SPSS version 22.0, we analysed the data with chi-square test, Fisher’s exact test and binomial logistic regression. RESULTS: Only 9.4% of the participants were male and 29.5% were aged 33-37 years. Just over 11% said they were worried about childhood vaccination, mainly because of the chemicals used in manufacturing the vaccines. The level of concern was greater among those who got information about vaccines from the internet, family members, friends, TV, radio, and newspapers. Those who used complementary health services were considerably more hesitant about vaccination than those who used mainstream services. CONCLUSIONS: Parents in Türkiye have several reasons for hesitating or refusing to vaccinate their children, key among which are concerns about the chemical composition of the vaccines and their ability to trigger negative health conditions such as autism. This study used a large sample size across Türkiye, although there were differences by region, the findings would be useful in designing interventions to counter vaccine hesitancy or refusal in the country.

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14. Wei P, Ahmedt-Aristizabal D, Gammulle H, Denman S, Armin MA. Vision-based activity recognition in children with autism-related behaviors. Heliyon;2023 (Jun);9(6):e16763.

Advances in machine learning and contactless sensors have enabled the understanding complex human behaviors in a healthcare setting. In particular, several deep learning systems have been introduced to enable comprehensive analysis of neuro-developmental conditions such as Autism Spectrum Disorder (ASD). This condition affects children from their early developmental stages onwards, and diagnosis relies entirely on observing the child’s behavior and detecting behavioral cues. However, the diagnosis process is time-consuming as it requires long-term behavior observation, and the scarce availability of specialists. We demonstrate the effect of a region-based computer vision system to help clinicians and parents analyze a child’s behavior. For this purpose, we adopt and enhance a dataset for analyzing autism-related actions using videos of children captured in uncontrolled environments (e.g. videos collected with consumer-grade cameras, in varied environments). The data is pre-processed by detecting the target child in the video to reduce the impact of background noise. Motivated by the effectiveness of temporal convolutional models, we propose both light-weight and conventional models capable of extracting action features from video frames and classifying autism-related behaviors by analyzing the relationships between frames in a video. By extensively evaluating feature extraction and learning strategies, we demonstrate that the highest performance is attained through the use of an Inflated 3D Convnet and Multi-Stage Temporal Convolutional Network. Our model achieved a Weighted F1-score of 0.83 for the classification of the three autism-related actions. We also propose a light-weight solution by employing the ESNet backbone with the same action recognition model, achieving a competitive 0.71 Weighted F1-score, and enabling potential deployment on embedded systems. Experimental results demonstrate the ability of our proposed models to recognize autism-related actions from videos captured in an uncontrolled environment, and thus can assist clinicians in analyzing ASD.

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15. Yu X, Wang Y. Peripheral Fragile X messenger ribonucleoprotein is required for the timely closure of a critical period for neuronal susceptibility in the ventral cochlear nucleus. Front Cell Neurosci;2023;17:1186630.

Alterations in neuronal plasticity and critical periods are common across neurodevelopmental diseases, including Fragile X syndrome (FXS), the leading single-gene cause of autism. Characterized with sensory dysfunction, FXS is the result of gene silencing of Fragile X messenger ribonucleoprotein 1 (FMR1) and loss of its product, Fragile X messenger ribonucleoprotein (FMRP). The mechanisms underlying altered critical period and sensory dysfunction in FXS are obscure. Here, we performed genetic and surgical deprivation of peripheral auditory inputs in wildtype and Fmr1 knockout (KO) mice across ages and investigated the effects of global FMRP loss on deafferentation-induced neuronal changes in the ventral cochlear nucleus (VCN) and auditory brainstem responses. The degree of neuronal cell loss during the critical period was unchanged in Fmr1 KO mice. However, the closure of the critical period was delayed. Importantly, this delay was temporally coincidental with reduced hearing sensitivity, implying an association with sensory inputs. Functional analyses further identified early-onset and long-lasting alterations in signal transmission from the spiral ganglion to the VCN, suggesting a peripheral site of FMRP action. Finally, we generated conditional Fmr1 KO (cKO) mice with selective deletion of FMRP in spiral ganglion but not VCN neurons. cKO mice recapitulated the delay in the VCN critical period closure in Fmr1 KO mice, confirming an involvement of cochlear FMRP in shaping the temporal features of neuronal critical periods in the brain. Together, these results identify a novel peripheral mechanism of neurodevelopmental pathogenesis.

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16. Zhou M, Zhang YM, Li T. Knowledge, attitudes and experiences of genetic testing for autism spectrum disorders among caregivers, patients, and health providers: A systematic review. World J Psychiatry;2023 (May 19);13(5):247-261.

BACKGROUND: Several genetic testing techniques have been recommended as a first-tier diagnostic tool in clinical practice for diagnosing autism spectrum disorder (ASD). However, the actual usage rate varies dramatically. This is due to various reasons, including knowledge and attitudes of caregivers, patients, and health providers toward genetic testing. Several studies have therefore been conducted worldwide to investigate the knowledge, experiences, and attitudes toward genetic testing among caregivers of children with ASD, adolescent and adult ASD patients, and health providers who provide medical services for them. However, no systematic review has been done. AIM: To systematically review research on knowledge, experiences, and attitudes towards genetic testing among caregivers of children with ASD, adolescent and adult ASD patients, and health providers. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and searched the literature in three English language databases (PubMed, Web of Science, and PsychInfo) and two Chinese databases (CNKI and Wanfang). Searched literature was screened independently by two reviewers and discussed when inconsistency existed. Information on characteristics of the study, characteristics of participants, and main findings regarding knowledge, experience, and attitudes of caregivers of children with ASD, adolescent and adult ASD patients, and health providers concerning ASD genetic testing were extracted from included papers into a charting form for analysis. RESULTS: We included 30 studies published between 2012 and 2022 and conducted in 9 countries. Most of the studies (n = 29) investigated caregivers of children with ASD, one study also included adolescent and adult patients, and two covered health providers. Most (51.0%-100%) of the caregivers/patients knew there was a genetic cause for ASD and 17.0% to 78.1% were aware of ASD genetic testing. However, they lacked full understanding of genetic testing. They acquired relevant and necessary information from physicians, the internet, ASD organizations, and other caregivers. Between 9.1% to 72.7% of caregivers in different studies were referred for genetic testing, and between 17.4% to 61.7% actually obtained genetic testing. Most caregivers agreed there are potential benefits following genetic testing, including benefits for children, families, and others. However, two studies compared perceived pre-test and post-test benefits with conflicting findings. Caregivers concerns included high costs, unhelpful results, negative influences (e.g., causing family conflicts, causing stress/risk/pain to children etc.) prevented some caregivers from using genetic testing. Nevertheless, 46.7% to 95.0% caregivers without previous genetic testing experience intended to obtain it in the future, and 50.5% to 59.6% of parents previously obtaining genetic testing would recommend it to other parents. In a single study of child and adolescent psychiatrists, 54.9% of respondents had ordered ASD genetic testing for their patients in the prior 12 mo, which was associated with greater knowledge of genetic testing. CONCLUSION: Most caregivers are willing to learn about and use genetic testing. However, the review showed their current knowledge is limited and usage rates varied widely in different studies.

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