What happens when children with autism grow? An exploratory study

Embora o focus de serviços e investigação na Perturbação do Espectro do Autismo (PEA) se centre na infância e adolescência, há um reconhecimento crescente que a PEA é uma perturbação que se mantem ao longo da vida. No entanto, embora os serviços de saúde, educação e sociais para crianças com PEA estejam estabelecidos, os recursos para adultos com esta perturbação são muito menos estruturados e evidenciam fragilidades. Neste estudo discutimos a estrutura organizacional de serviços para adultos com PEA em Portugal e exploramos as práticas relativamente ao desenvolvimento de abordagens multidisciplinares, à gestão das comorbilidades, à gestão das transições durante a vida adulta e ao cuidado do idoso com PEA, e identificamos ações que melhorem o acesso ao diagnóstico e suporte pós-diagnóstico. Para o efeito, contactámos 15 instituições envolvidas em cuidados de adultos com PEA em Portugal e sintetizamos as principais ideias expressas pelos informantes relativamente ao que está a ser feito em Portugal. Concluímos que é necessária uma investigação mais sistematizada e detalhada sobre os serviços de apoio a adultos com PEA; em particular, é necessário obter mais evidência sobre as necessidades desta população relativamente à saúde, ocupação, residência, transições de vida e envelhecimento, de forma a programar e implementar soluções adequadas para o adulto que tenham em consideração as suas capacidades e competências.Although Autism Spectrum Disorder (ASD) ser vices and research are focused primarily on children, there is increasing recognition that ASD is a lifelong disorder. However, although health, education and social ser vices for children with ASD are relatively well established, ser vice provision for adults with ASD still shows many weaknesses, and concrete information on best practices is scarse. In this study, we discuss the organizational structure of ser vices for adults with ASD in Por tugal and explore the current practices for the development of multidisciplinar y suppor t approaches, for management of co-morbidity, for the management of transitions during adult life and for care for the autistic elder, and identif y actions that improve access to diagnosis and post-diagnostic suppor t. To gather qualitative information on these issues, we have contacted 15 institutions involved in adult care in Por tugal, and synthesize the main ideas expressed by key informants regarding what is being done in Por tugal. We conclude that fur ther detailed investigation of ser vice provision for adults with PEA is required. In par ticular, there is a need to better understand the needs of adults with ASD, including health, occupation, transitions, aging and residential solutions, in order to provide evidence for the development and implementation of adequate resources for adults that take into account their skills and competencies.info:eu-repo/semantics/publishedVersio

Complex associations between genetic variants and clinical profiles in autism spectrum disorder patients: an integrative systems biology approach

A complexidade genética e clínica que caracterizam a per turbação do espetro do autismo (PEA) têm limitado o desenvolvimento de biomarcadores que permitam um diagnóstico precoce e um prognóstico fiável, assim como uma abordagem personalizada para a inter venção terapêutica. Neste estudo pretendeu-se desenvolver uma abordagem integrativa para predição da apresentação clínica baseada em informação de variantes genéticas (Copy Number Variants, CNVs), com aplicação clínica no diagnóstico e prognóstico na PEA. Para tal, técnicas de aprendizagem automática (machine learning) foram aplicadas a dados clínicos e genéticos de 2446 doentes com PEA, recrutados no âmbito do consórcio Autism Genome Project. Análise de clustering de dados clínicos multidimensionais definiu, nesta população, dois subgrupos de pacientes com per fis clínicos diferindo significativamente em termos de capacidade verbal, nível cognitivo, gravidade da doença e compor tamento adaptativo. A análise dos CNVs que afetam especificamente genes do cérebro, nos mesmos indivíduos, identificou 15 processos biológicos enriquecidos em genes alterados. A aplicação de um algoritmo de machine learning para classificação dos doentes com apresentação clínica mais disfuncional, com base nos processos biológicos alterados, mostrou que correlações entre fenótipo clínico e biologia subjacente são possíveis na PEA e que, para grupos populacionais com dados informativos, existe um poder preditivo razoável. Para implementação deste conceito na prática clínica serão necessários estudos mais alargados com dados clínicos e genómicos mais completos.The genetic and clinical complexity that characterize Autism Spectrum Disorder (ASD) has hindered the development of biomarkers for early diagnosis and reliable prognosis, as well as a personalized to therapeutic inter vention. This study aimed to develop an integrative approach for clinical presentation prediction based on Copy Number Variants (CNVs), with clinical application for diagnosis and prognosis of ASD. For this purpose, machine learning techniques were applied to a dataset of 2446 patients with ASD, recruited by the Autism Genome Project. Clustering analysis of multidimensional clinical data allowed the definition of two patient subgroups in this population, with clinical profiles dif fering significantly in verbal ability, cognitive level, disease severity and adaptive behavior. In the same subjects, analysis of CNVs specifically af fecting brain-expressed genes identified 15 biological processes enriched for the disrupted genes. A machine learning algorithm was trained and tested to classif y patients with more dysfunctional clinical presentation based on altered biological processes. The results showed that correlations between clinical phenotype and underlying biology can be established in ASD and that, for datasets with suf ficiently informative data, there is a reasonable predictive power. Fur ther studies with more complete clinical and genomic data are needed to implement this concept in clinical practice.info:eu-repo/semantics/publishedVersio

Hope for GWAS: Relevant Risk Genes Uncovered from GWAS Statistical Noise

Hundreds of genetic variants have been associated to common diseases through genome-wide association studies (GWAS), yet there are limits to current approaches in detecting true small effect risk variants against a background of false positive findings. Here we addressed the missing heritability problem, aiming to test whether there are indeed risk variants within GWAS statistical noise and to develop a systematic strategy to retrieve these hidden variants. Employing an integrative approach, which combines protein-protein interactions with association data from GWAS for 6 common diseases, we found that associated-genes at less stringent significance levels (p < 0.1) with any of these diseases are functionally connected beyond noise expectation. This functional coherence was used to identify disease-relevant subnetworks, which were shown to be enriched in known genes, outperforming the selection of top GWAS genes. As a proof of principle, we applied this approach to breast cancer, supporting well-known breast cancer genes, while pinpointing novel susceptibility genes for experimental validation. This study reinforces the idea that GWAS are under-analyzed and that missing heritability is rather hidden. It extends the use of protein networks to reveal this missing heritability, thus leveraging the large investment in GWAS that produced so far little tangible gain.FCT: SFRH/BPD/64281/2009

Gene-environment interactions in autism spectrum disorder

A Perturbação do Espetro do Autismo (PEA) tem uma heritabilidade estimada de 50%, indicativa de uma componente genética que pode ser modulada por fatores ambientais. A evidência de associação com autismo de alguns compostos potencialmente tóxicos levou-nos a colocar a hipótese de que genes envolvidos em processos de destoxificação e regulação da permeabilidade de barreiras fisiológicas (p. ex. placenta, hematoencefálica) são candidatos para a PEA. Neste trabalho definimos uma lista de 519 genes de destoxificação e das barreiras de permeabilidade, e comparamos a frequência de Copy Number Variants (CNVs) nestes genes em 2446 crianças com PEA, recrutadas através do Autism Genome Project (AGP), com 10355 controlos sem patologia neuropsiquiátrica da Database of Genomic Variants. Como validação, foram avaliados indivíduos com PEA da Simons Foundation Autism Research Initiative (SFARI) (N=1124). Verificouse que 555 (22,7%) indivíduos com PEA apresentavam CNVs contendo 173 dos 519 genes de interesse, 31 dos quais foram encontrados exclusivamente em pacientes com PEA, enquanto 23 genes eram significativamente mais frequentes em CNVs de indivíduos com PEA do que em controlos. Múltiplos dos genes identificados estão envolvidos no transporte através de barreiras fisiológicas ou na destoxificação de toxinas relevantes para a PEA. Este estudo reforça a hipótese de que, em indivíduos geneticamente suscetíveis, a exposição a fatores ambientais potencialmente tóxicos pode contribuir para a PEA.Autism Spectrum Disorder (ASD) has an estimated heritability of 50%, indicating a genetic component that may be modulated by the environment. Recent studies implicate exposure to specific toxins in ASD etiology. We thus hypothesize that genes involved in detoxification and regulation of physiological barrier permeability processes (e.g. placenta, blood-brain barrier) are plausible candidates for ASD etiology. In this study we defined a candidate list of 519 detoxification and barrier permeability genes that may interact with toxicants relevant for ASD. We compared the frequency of Copy Number Variants (CNVs) targeting these genes in 2446 ASD patients, recruited through the Autism Genome Project, and 10355 controls without neuropsychiatric disease from the Database of Genomic Variants, and validated results in 1124 ASD subjects from the Simons Foundation Autism Research Initiative. We found that 173 of the 519 detoxification and barrier genes were targeted by CNVs from 555 (22.7%) individuals with ASD. Of these genes, 31 were exclusively targeted by CNVs in ASD subjects and 23 were significantly more frequent in ASD than in controls. Network analysis showed that many of these genes are involved in the transport through physiological barriers or the detoxification of potential toxicants relevant for ASD. This study reinforces the hypothesis that the exposure to environmental factors in genetically susceptible individuals may contribute to ASD risk.info:eu-repo/semantics/publishedVersio

CNV Characterization, Inheritance and Phenotypic Correlations in Families With Autism

Autism Spectrum Disorders (ASD) have a strong genetic component, with an estimated heritability of over 90%1. Recent studies carried out by the Autism Genome Project (AGP) consortium suggest that rare Copy Number Variants (CNVs), characterized by submicroscopic chromosomal deletions and duplications, are more frequent in ASD compared to controls, and may play an important role in susceptibility to this disorder2. However, to adequately assess pathogenicity, a detailed characterization of patients CNVs and phenotype is required. The goal of this study was to establish the clinical and etiological relevance for ASD of potentially pathogenic CNVs identified in a Portuguese population sample by whole genome CNV analysis, through the detailed characterization of CNVs and correlation with clinical phenotypes. Analysis of the AGP genome-wide CNV results using 1M SNP microarray2 identified a total of 14218 CNVs in 342 Portuguese probands. We selected 291 CNVs, present in 191 individuals (19 females and 172 males), using the following criteria: 1) CNVs that contained implicated/candidate genes for ASD; 2) CNVs in genomic regions known to be implicated/candidate for ASD; 3) CNVs in regions associated with syndromes with ASD symptoms; and 4) high confidence CNVs that did not overlap more than 20% with controls in available databases. We explored recurrence rates, genic content, regulatory elements, inheritance patterns and phenotypic correlations.This work was supported by the fellowships SFRH/BPD/74739/2010 to ICC, SFRH/BPD/64281/2009 to CC and SFRH/BD/79081/2011 to BO from Fundação para a Ciência e a Tecnologia (Portugal)

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.Fundação para a Ciência e Tecnologia - FCTinfo:eu-repo/semantics/publishedVersio

Relevance of Common and Rare CNVs for Autism Etiology

Recent reports by the Autism Genome Project (AGP) consortium and other groups show that Copy Number Variants (CNVs), while individually rare, collectively may explain a large fraction of the etiology of Autism Spectrum Disorders (ASD). The goal of this study was to establish the clinical and etiological relevance for ASD of potentially pathogenic CNVs identified in a Portuguese population sample by whole genome CNV analysis, through the detailed characterization of CNVs and correlation with clinical phenotypes. Analysis of the Autism Genome Project genome-wide CNV results using 1M SNP microarray1 identified a total of 14218 CNVs in 342 Portuguese probands. We selected 292 CNVs, present in 191 individuals (19 females and 172 males), using the following criteria: 1) CNVs that contained implicated/candidate genes for ASD; 2) CNVs in genomic regions known to be implicated/candidate for ASD; 3) CNVs containing genes associated with syndromes with ASD symptoms; and 4) high confidence CNVs that did not overlap more than 20% with controls in available databases. We explored recurrence rates, genic content, regulatory elements, inheritance patterns and clinical correlationsThis work was supported by the fellowships SFRH/BPD/74739/2010 to ICC, SFRH/BPD/64281/2009 to CC and SFRH/BD/79081/2011 to BO from Fundação para a Ciência e a Tecnologia (FCT; Portugal)