Bridging Genetic Insights with Neuroimaging in Autism Spectrum Disorder-A Systematic Review.

Autism Spectrum Disorder (ASD) is an early onset neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive patterns of behavior. Family studies show that ASD is highly heritable, and hundreds of genes have previously been implicated in the disorder; however, the etiology is still not fully clear. Brain imaging and electroencephalography (EEG) are key techniques that study alterations in brain structure and function. Combined with genetic analysis, these techniques have the potential to help in the clarification of the neurobiological mechanisms contributing to ASD and help in defining novel therapeutic targets. To further understand what is known today regarding the impact of genetic variants in the brain alterations observed in individuals with ASD, a systematic review was carried out using Pubmed and EBSCO databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This review shows that specific genetic variants and altered patterns of gene expression in individuals with ASD may have an effect on brain circuits associated with face processing and social cognition, and contribute to excitation-inhibition imbalances and to anomalies in brain volumes.

Identification of Neurotransmission and Synaptic Biological Processes Disrupted in Autism Spectrum Disorder Using Interaction Networks and Community Detection Analysis.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by communication deficits and repetitive behavioral patterns. Hundreds of candidate genes have been implicated in ASD, including neurotransmission and synaptic (NS) genes; however, the genetic architecture of this disease is far from clear. In this study, we seek to clarify the biological processes affected by NS gene variants identified in individuals with ASD and the global networks that link those processes together. For a curated list of 1216 NS candidate genes, identified in multiple databases and the literature, we searched for ultra-rare (UR) loss-of-function (LoF) variants in the whole-exome sequencing dataset from the Autism Sequencing Consortium (N = 3938 cases). Filtering for population frequency was carried out using gnomAD (N = 60,146 controls). NS genes with UR LoF variants were used to construct a network of protein-protein interactions, and the network's biological communities were identified by applying the Leiden algorithm. We further explored the expression enrichment of network genes in specific brain regions. We identified 356 variants in 208 genes, with a preponderance of UR LoF variants in the PDE11A and SYTL3 genes. Expression enrichment analysis highlighted several subcortical structures, particularly the basal ganglia. The interaction network defined seven network communities, clustering synaptic and neurotransmitter pathways with several ubiquitous processes that occur in multiple organs and systems. This approach also uncovered biological pathways that are not usually associated with ASD, such as brain cytochromes P450 and brain mitochondrial metabolism. Overall, the community analysis suggests that ASD involves the disruption of synaptic and neurotransmitter pathways but also ubiquitous, but less frequently implicated, biological processes.

Prevalence of Autism Spectrum Disorder in the Centro region of Portugal: a population based study of school age children within the ASDEU project.

Introduction: Accurate prevalence estimates for Autism Spectrum Disorder (ASD) are fundamental to adequately program medical and educational resources for children. However, estimates vary globally and across Europe, and it is therefore wise to conduct epidemiological studies in defined geo-cultural contexts. Methods: We used a population screening approach to estimate the prevalence of ASD in the Centro region of Portugal, using a harmonized protocol as part of the Autism Spectrum Disorders in the European Union (ASDEU) project. Results: The overall prevalence was estimated at 0.5% (95% CI 0.3-0.7), higher in schools with Autism Units (3.3%, 95%CI 2.7-3.9) than in regular schools (0.3%, 95% CI 0.1-0.5) or schools with Multiple Disability Units (0.3%, 95% CI 0.04-0.6). Discussion: The results indicate that the diagnosis of ASD is followed by the most effective educational policies in Centro Region. The variability in prevalence estimates across the different regions from the ASDEU project, and globally, is discussed.

Evidence for an association of prenatal exposure to particulate matter with clinical severity of Autism Spectrum Disorder.

Early-life exposure to air pollutants, including ozone (O3), particulate matter (PM2.5 or PM10, depending on diameter of particles), nitrogen dioxide (NO2) and sulfur dioxide (SO2) has been suggested to contribute to the etiology of Autism Spectrum Disorder (ASD). In this study, we used air quality monitoring data to examine whether mothers of children with ASD were exposed to high levels of air pollutants during critical periods of pregnancy, and if higher exposure levels may lead to a higher clinical severity in their offspring. We used public data from the Portuguese Environment Agency to estimate exposure to these pollutants during the first, second and third trimesters of pregnancy, full pregnancy and first year of life of the child, for 217 subjects with ASD born between 2003 and 2016. These subjects were stratified in two subgroups according to clinical severity, as defined by the Autism Diagnostic Observational Schedule (ADOS). For all time periods, the average levels of PM2.5, PM10 and NO2 to which the subjects were exposed were within the admissible levels defined by the European Union. However, a fraction of these subjects showed exposure to levels of PM2.5 and PM10 above the admissible threshold. A higher clinical severity was associated with higher exposure to PM2.5 (p = 0.001), NO2 (p = 0.011) and PM10 (p = 0.041) during the first trimester of pregnancy, when compared with milder clinical severity. After logistic regression, associations with higher clinical severity were identified for PM2.5 exposure during the first trimester (p = 0.002; OR = 1.14, 95%CI: 1.05-1.23) and full pregnancy (p = 0.04; OR = 1.07, 95%CI: 1.00-1.15) and for PM10 (p = 0.02; OR = 1.07, 95%CI: 1.01-1.14) exposure during the third trimester. Exposure to PM is known to elicit neuropathological mechanisms associated with ASD, including neuroinflammation, mitochondrial disruptions, oxidative stress and epigenetic changes. These results offer new insights on the impact of early-life exposure to PM in ASD clinical severity.

Mental Health of Healthcare Professionals: Two Years of the COVID-19 Pandemic in Portugal.

The COVID-19 pandemic increased psychosocial risk factors among healthcare professionals (HCPs). Objective: To characterize Portuguese HCPs mental health (MH), estimate anxiety, depression, post-traumatic stress disorder (PTSD) and burnout symptoms, and identify risk/protective factors. A cross-sectional online survey and a longitudinal assessment were conducted in 2020 (T0) and 2021 (T1). Sociodemographic and occupational variables, COVID-19-related experiences and protective behavior data were collected from a non-probabilistic sample of HCPs in Portugal. Symptoms of anxiety, depression, PTSD, burnout and resilience were assessed using the Portuguese versions of the Generalized Anxiety Disorder Scale (GAD-7), the Patient Health Questionnaire (PHQ-9), the Post-traumatic Stress Disorder Checklist (PCL-5), the Shirom-Melamed Burnout Measure (MBSM) and the Connor-Davidson Resilience Scale (CD-RISC-10), respectively. Risk and protective factors were identified through simple and multiple logistic regression models. Overall, 2027 participants answered the survey in T0 and 1843 in T1. The percentage of moderate-to-severe symptoms decreased from T0 to T1; however, a considerable proportion of HCPs reported symptoms of distress in both years. Being a woman, working in a COVID-19-treatment frontline position and work-life balance increased the odds of distress. High resilience, good social/family support, and hobbies/lifestyle maintenance were found to be protective factors. Globally, our results show that performing as a HCP during the pandemic may result in long-term effects on MH.

Disease similarity network analysis of Autism Spectrum Disorder and comorbid brain disorders.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with heterogeneous clinical presentation, variable severity, and multiple comorbidities. A complex underlying genetic architecture matches the clinical heterogeneity, and evidence indicates that several co-occurring brain disorders share a genetic component with ASD. In this study, we established a genetic similarity disease network approach to explore the shared genetics between ASD and frequent comorbid brain diseases (and subtypes), namely Intellectual Disability, Attention-Deficit/Hyperactivity Disorder, and Epilepsy, as well as other rarely co-occurring neuropsychiatric conditions in the Schizophrenia and Bipolar Disease spectrum. Using sets of disease-associated genes curated by the DisGeNET database, disease genetic similarity was estimated from the Jaccard coefficient between disease pairs, and the Leiden detection algorithm was used to identify network disease communities and define shared biological pathways. We identified a heterogeneous brain disease community that is genetically more similar to ASD, and that includes Epilepsy, Bipolar Disorder, Attention-Deficit/Hyperactivity Disorder combined type, and some disorders in the Schizophrenia Spectrum. To identify loss-of-function rare de novo variants within shared genes underlying the disease communities, we analyzed a large ASD whole-genome sequencing dataset, showing that ASD shares genes with multiple brain disorders from other, less genetically similar, communities. Some genes (e.g., SHANK3, ASH1L, SCN2A, CHD2, and MECP2) were previously implicated in ASD and these disorders. This approach enabled further clarification of genetic sharing between ASD and brain disorders, with a finer granularity in disease classification and multi-level evidence from DisGeNET. Understanding genetic sharing across disorders has important implications for disease nosology, pathophysiology, and personalized treatment.

A Role for Gene-Environment Interactions in Autism Spectrum Disorder Is Supported by Variants in Genes Regulating the Effects of Exposure to Xenobiotics.

Heritability estimates support the contribution of genetics and the environment to the etiology of Autism Spectrum Disorder (ASD), but a role for gene-environment interactions is insufficiently explored. Genes involved in detoxification pathways and physiological permeability barriers (e.g., blood-brain barrier, placenta and respiratory airways), which regulate the effects of exposure to xenobiotics during early stages of neurodevelopment when the immature brain is extremely vulnerable, may be particularly relevant in this context. Our objective was to identify genes involved in the regulation of xenobiotic detoxification or the function of physiological barriers (the XenoReg genes) presenting predicted damaging variants in subjects with ASD, and to understand their interaction patterns with ubiquitous xenobiotics previously implicated in this disorder. We defined a panel of 519 XenoReg genes through literature review and database queries. Large ASD datasets were inspected for in silico predicted damaging Single Nucleotide Variants (SNVs) (N = 2,674 subjects) or Copy Number Variants (CNVs) (N = 3,570 subjects) in XenoReg genes. We queried the Comparative Toxicogenomics Database (CTD) to identify interaction pairs between XenoReg genes and xenobiotics. The interrogation of ASD datasets for variants in the XenoReg gene panel identified 77 genes with high evidence for a role in ASD, according to pre-specified prioritization criteria. These include 47 genes encoding detoxification enzymes and 30 genes encoding proteins involved in physiological barrier function, among which 15 are previous reported candidates for ASD. The CTD query revealed 397 gene-environment interaction pairs between these XenoReg genes and 80% (48/60) of the analyzed xenobiotics. The top interacting genes and xenobiotics were, respectively, CYP1A2, ABCB1, ABCG2, GSTM1, and CYP2D6 and benzo-(a)-pyrene, valproic acid, bisphenol A, particulate matter, methylmercury, and perfluorinated compounds. Individuals carrying predicted damaging variants in high evidence XenoReg genes are likely to have less efficient detoxification systems or impaired physiological barriers. They can therefore be particularly susceptible to early life exposure to ubiquitous xenobiotics, which elicit neuropathological mechanisms in the immature brain, such as epigenetic changes, oxidative stress, neuroinflammation, hypoxic damage, and endocrine disruption. As exposure to environmental factors may be mitigated for individuals with risk variants, this work provides new perspectives to personalized prevention and health management policies for ASD.

Autistic Adult Services Availability, Preferences, and User Experiences: Results From the Autism Spectrum Disorder in the European Union Survey.

There is very little knowledge regarding autistic adult services, practices, and delivery. The study objective was to improve understanding of current services and practices for autistic adults and opportunities for improvement as part of the Autism Spectrum Disorder in the European Union (ASDEU) project. Separate survey versions were created for autistic adults, carers of autistic adults, and professionals in adult services. 2,009 persons responded to the survey and 1,085 (54%) of them completed at least one of the services sections: 469 autistic adults (65% female; 55% <35 years old), 441 carers of autistic adults (27% female; 6% <35 years old), 175 professionals in adult services (76% female; 67% in non-medical services). Top choices by autistic adults, carers or professionals for services best suiting their current needs were: residential services: "help in own home" (adults, carers of high independent adults, professionals), "fulltime residential facility" (carers of low independent adults); employment services: "job mentors" (adults, carers of high independent adults, professionals), "Sheltered employment" (carers of low independent adults); education services: "support in regular education setting" (all groups); financial services: financial support in lieu of employment ("Supplementary income for persons unable to have full employment" for adults, "full pension" for carers of low independent adults) or to supplement employment earnings for carers of high independent adults and professionals; social services: "behavior training" (adults) and "life skills training" (carers and professionals). Waiting times for specific services were generally < 1 month or 1-3 months, except for residential services which could be up to 6 months; most professionals were uninformed of waiting times (>50% responded "don't know"). Five of seven residential services features recommended for autistic adults were experienced by <50% of adults. The knowledge of good local services models that work well for autistic adults was generally low across all services areas. The variation in services experiences and perceptions reported by autistic adults, carers, or professionals underscore the need to query all groups for a complete picture of community services availability and needs. The results showed areas for potential improvement in autistic adult services delivery in the EU to achieve recommended standards.

Determinants of satisfaction with the detection process of autism in Europe: Results from the ASDEU study.

LAY ABSTRACT: Professional guidance and support in response to first concerns appears to be an important predictor of the level of satisfaction with the detection process of autism in young children. In this study, we analyzed the views of 1342 family members, including 1278 parents, who completed an online survey form collecting information about their experience and satisfaction with the early detection of autism in their child. Specifically, we were interested in how specific experiences with the detection process relate to the satisfaction with it and whether we could identify important predictors of satisfaction. The detection process is an emotionally charged period for parents, often described as painful, chaotic, and lengthy. A better understanding of their experiences is important to take appropriate action to improve the detection process. In our sample, the level of satisfaction with the detection process varied greatly from one respondent to another. Among the different experiences we considered, whether or not respondents received professional guidance and support in response to first concerns explained most of this variation. We also found that difficulty finding information about detection services, lack of professional guidance and support in response to first concerns, having to find a diagnostic service on one's own, and longer delays between confirmation of concerns and first appointment with a specialist were experiences associated with a greater likelihood of being unsatisfied. The findings of this study highlight the importance of the parent-professional relationship in the detection process and have important practical implications for health administrations to improve the detection process.

Gene Variants Involved in Nonsense-Mediated mRNA Decay Suggest a Role in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition with unclear etiology. Many genes have been associated with ASD risk, but the underlying mechanisms are still poorly understood. An important post-transcriptional regulatory mechanism that plays an essential role during neurodevelopment, the Nonsense-Mediated mRNA Decay (NMD) pathway, may contribute to ASD risk. In this study, we gathered a list of 46 NMD factors and regulators and investigated the role of genetic variants in these genes in ASD. By conducting a comprehensive search for Single Nucleotide Variants (SNVs) in NMD genes using Whole Exome Sequencing data from 1828 ASD patients, we identified 270 SNVs predicted to be damaging in 28.7% of the population. We also analyzed Copy Number Variants (CNVs) from two cohorts of ASD patients (N = 3570) and discovered 38 CNVs in 1% of cases. Importantly, we discovered 136 genetic variants (125 SNVs and 11 CNVs) in 258 ASD patients that were located within protein domains required for NMD. These gene variants are classified as damaging using in silico prediction tools, and therefore may interfere with proper NMD function in ASD. The discovery of NMD genes as candidates for ASD in large patient genomic datasets provides evidence supporting the involvement of the NMD pathway in ASD pathophysiology.

Intervention Services for Autistic Adults: An ASDEU Study of Autistic Adults, Carers, and Professionals' Experiences.

The Autism Spectrum Disorders in the European Union (ASDEU) survey investigated local services' use experiences of autistic adults, carers and professionals with interventions for autistic adults. The majority of the 697 participants experienced recommended considerations prior to deciding on intervention and during the intervention plan and implementation. Psychosocial interventions were the most commonly experienced interventions, while pharmacological interventions NOT recommended for core autistic symptoms were reported by fairly large proportions of participants. Family interventions were experienced slightly more commonly by carers than adults or professionals. Less than the 26% of autistic adult responders who had experienced challenging behaviors reported receiving an intervention to change them. These results provide insights for improving gaps in service provision of interventions among autistic adults.

Autistic Adult Health and Professional Perceptions of It: Evidence From the ASDEU Project.

The Autism Spectrum Disorders in the European Union (ASDEU) survey investigated the knowledge and health service experiences of users and providers to generate new hypotheses and scientific investigations that would contribute to improvement in health care for autistic adults. An online survey designed for autistic adults, carers of autistic adults, and professionals in adult services was translated into 11 languages and distributed electronically by organizations and in-country adult service facilities in 2017; 522 autistic adults, 442 carers, and 113 professionals provided answers to the health questions. Professionals, the majority in non-medical services, appeared to be poorly informed about whether certain co-occurring conditions were more frequent in autistic adults than typical adults-especially some medical conditions, suicide attempts, accidents, and pain. A minority of autistic adults reported preventive health behaviors such as routine health check-ups. The majority of users and providers expressed the desire to make health care services more user-friendly for autistic adults. Among the three groups, <20% of responders knew an organization or clinician which has developed a way to monitor health, and prevent poor health, that works well for adults on the autism spectrum. The results point to means for better management of co-occurring conditions associated with autism in adulthood in order to reduce hospital admissions and potential areas of improvement in health and social services for autistic adults. Specifically, efforts should be focused on (1) professionals' education on risks for co-occurring conditions in autistic adults; (2) promoting preventive health behaviors; (3) making services user-friendly for autistic adults and their families; and (4) encouraging knowledge of good local services.

Real-World Experiences in Autistic Adult Diagnostic Services and Post-diagnostic Support and Alignment with Services Guidelines: Results from the ASDEU Study.

Research providing an evidence-base for autistic adult services is sparse. The Autism Spectrum Disorders in the European Union (ASDEU) network implemented an on-line survey to determine gaps in autistic adult diagnostic evaluation and post-diagnostic support services. More than 55% in all groups experienced most of the recommended features for diagnostic evaluation for autistic adults. In contrast, < 2% of adults or carers, and < 21% of professionals experienced each of the recommended features for post-diagnostic support. In contrast to 61% of professionals, only about 30% of autistic adults and carers had knowledge of good local services models for autism diagnosis in adulthood. There are major differences between good practice guidelines for diagnostic and post-diagnostic care for autistic adults, and what is actually experienced by services users and professionals.

The role of rare compound heterozygous events in autism spectrum disorder.

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X2 = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X2 = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, ß = 0.13; p = 1.0 × 10-5). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.

How personalised medicine will transform healthcare by 2030: the ICPerMed vision.

This commentary presents the vision of the International Consortium for Personalised Medicine (ICPerMed) on how personalised medicine (PM) will lead to the next generation of healthcare by 2030. This vision focuses on five perspectives: individual and public engagement, involvement of health professionals, implementation within healthcare systems, health-related data, and the development of sustainable economic models that allow improved therapy, diagnostic and preventive approaches as new healthcare concepts for the benefit of the public. We further identify four pillars representing transversal issues that are crucial for the successful implementation of PM in all perspectives. The implementation of PM will result in more efficient and equitable healthcare, access to modern healthcare methods, and improved control by individuals of their own health data, as well as economic development in the health sector.

Identification of biological mechanisms underlying a multidimensional ASD phenotype using machine learning.

The complex genetic architecture of Autism Spectrum Disorder (ASD) and its heterogeneous phenotype makes molecular diagnosis and patient prognosis challenging tasks. To establish more precise genotype-phenotype correlations in ASD, we developed a novel machine-learning integrative approach, which seeks to delineate associations between patients' clinical profiles and disrupted biological processes, inferred from their copy number variants (CNVs) that span brain genes. Clustering analysis of the relevant clinical measures from 2446 ASD cases in the Autism Genome Project identified two distinct phenotypic subgroups. Patients in these clusters differed significantly in ADOS-defined severity, adaptive behavior profiles, intellectual ability, and verbal status, the latter contributing the most for cluster stability and cohesion. Functional enrichment analysis of brain genes disrupted by CNVs in these ASD cases identified 15 statistically significant biological processes, including cell adhesion, neural development, cognition, and polyubiquitination, in line with previous ASD findings. A Naive Bayes classifier, generated to predict the ASD phenotypic clusters from disrupted biological processes, achieved predictions with a high precision (0.82) but low recall (0.39), for a subset of patients with higher biological Information Content scores. This study shows that milder and more severe clinical presentations can have distinct underlying biological mechanisms. It further highlights how machine-learning approaches can reduce clinical heterogeneity by using multidimensional clinical measures, and establishes genotype-phenotype correlations in ASD. However, predictions are strongly dependent on patient's information content. Findings are therefore a first step toward the translation of genetic information into clinically useful applications, and emphasize the need for larger datasets with very complete clinical and biological information.

Early Detection, Diagnosis and Intervention Services for Young Children with Autism Spectrum Disorder in the European Union (ASDEU): Family and Professional Perspectives.

Early services for ASD need to canvas the opinions of both parents and professionals. These opinions are seldom compared in the same research study. This study aims to ascertain the views of families and professionals on early detection, diagnosis and intervention services for young children with ASD. An online survey compiled and analysed data from 2032 respondents across 14 European countries (60.9% were parents; 39.1% professionals). Using an ordinal scale from 1 to 7, parents' opinions were more negative (mean = 4.6; SD 2.2) compared to those of professionals (mean = 4.9; SD 1.5) when reporting satisfaction with services. The results suggest services should take into account child's age, delays in accessing services, and active stakeholders' participation when looking to improve services.

Correction to: Early Detection, Diagnosis and Intervention Services for Young Children with Autism Spectrum Disorder in the European Union (ASDEU): Family and Professional Perspectives.

The original version of this article unfortunately contained a mistake in one of the co-author's family name. The correct name should be María Victoria Martín-Cilleros instead of María Victoria Cilleros-Martín.