Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011;1380:42-77

INSERM, U952, Université Pierre et Marie Curie, Paris, France.
Brain research (Impact Factor: 2.84). 12/2010; 1380:42-77. DOI: 10.1016/j.brainres.2010.11.078
Source: PubMed


There is increasing evidence that autism spectrum disorders (ASDs) can arise from rare highly penetrant mutations and genomic imbalances. The rare nature of these variants, and the often differing orbits of clinical and research geneticists, can make it difficult to fully appreciate the extent to which we have made progress in understanding the genetic etiology of autism. In fact, there is a persistent view in the autism research community that there are only a modest number of autism loci known. We carried out an exhaustive review of the clinical genetics and research genetics literature in an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD. We provide data on 103 disease genes and 44 genomic loci reported in subjects with ASD or autistic behavior. These genes and loci have all been causally implicated in intellectual disability, indicating that these two neurodevelopmental disorders share common genetic bases. A genetic overlap between ASD and epilepsy is also apparent in many cases. Taken together, these findings clearly show that autism is not a single clinical entity but a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders. Increased recognition of the etiological heterogeneity of ASD will greatly expand the number of target genes for neurobiological investigations and thereby provide additional avenues for the development of pathway-based pharmacotherapy. Finally, the data provide strong support for high-resolution DNA microarrays as well as whole-exome and whole-genome sequencing as critical approaches for identifying the genetic causes of ASDs.

15 Reads
  • Source
    • "O transtorno se manifesta precocemente no desenvolvimento e possui taxa de prevalência de 0,5% da população (Associação Americana de Psiquiatria, 2014; Fombonne, 2009). Do ponto de vista genético, o autismo é considerado um transtorno heterogêneo, na medida em que envolve a interação de múltiplos genes, que juntos levam à predisposição à manifestação do transtorno em sua forma completa (Betancur, 2011). Desde o estudo de Folstein e Rutter (1977), no qual as bases genéticas do autismo foram demonstradas de forma convincente pela primeira vez, evidências vêm sendo acumuladas neste sentido. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resumo O autismo pode ser defi nido como uma síndrome comportamental heterogênea em termos genéticos e de diagnóstico. Esta heterogeneidade difi culta a realização de estudos genéticos sobre o tema. Um dos endofenótipos candidatos do autismo é a teoria da mente. O objetivo deste estudo foi avaliar a capacidade da teoria da mente em pais de crianças com autismo. Foram avaliados 90 participantes: 30 pais de crianças com autismo, 30 pais de crianças com síndrome de Down e 30 pais de crianças com desenvolvimento típico. Os instrumentos utilizados foram o Eyes Test, para avaliar habilidades de decodifi cação, e o Unexpected Outcomes Task, para medir o raciocínio dedutivo. Os resultados não indicam diferenças signifi cativas entre os grupos na habilidade de decodifi cação. No entanto, eles indicam a existência de défi cits na capacidade de dedução da teoria da mente. Esse défi cit parece ser mais pronunciado em mães de crianças com autismo, em comparação com grupos de mães de crianças com síndrome de Down e mães de crianças com desenvolvimento típico. Mais estudos são necessários para esclarecer melhor a relação entre teoria da mente e autismo. Palavras-chave: Teoria da mente, autismo, avaliação, pais. Abstract Autism can be defi ned as a heterogeneous behavioral syndrome in both genetic and diagnostic terms. This heterogeneity poses diffi culties in conducting genetic studies on the topic. A candidate endo-phenotype of autism is theory of mind. The goal of this study was to evaluate the ability of theory of mind in parents of children with autism. We evaluated 90 participants: 30 parents of children with autism, 30 parents of children with Down syndrome and 30 parents of typically developing children. The instruments used were the Eyes Test, to assess decoding skills, and the Unexpected Outcomes Task, to measure deductive reasoning. The results do not indicate signifi cant differences between groups in theory of mind decoding. However, they indicate the existence of defi cits in the theory of mind reasoning. These defi cits seem to be more pronounced in mothers of children with autism, compared to groups of mothers of children with Down syndrome and mothers of typically developing children. Further studies are needed to better clarify the relationship between theory of mind and autism.
    Psicologia: Reflexao e Critica 11/2015; 28(4):789-795. DOI:10.1590/1678-7153.201528417
  • Source
    • "Current estimates indicate there will be several hundred genes implicated by this approach when sufficient sample size is obtained ( Krumm et al . , 2014 ) , in addition to the >100 genetic syndromes which already show some shared genetics or comorbidity with ASD ( Betancur , 2011 ; Yu et al . , 2013 ) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The substantial progress in the last few years toward uncovering genetic causes and risk factors for autism spectrum disorders (ASDs) has opened new experimental avenues for identifying the underlying neurobiological mechanism of the condition. The bounty of genetic findings has led to a variety of data-driven exploratory analyses aimed at deriving new insights about the shared features of these genes. These approaches leverage data from a variety of different sources such as co-expression in transcriptomic studies, protein–protein interaction networks, gene ontologies (GOs) annotations, or multi-level combinations of all of these. Here, we review the recurrent themes emerging from these analyses and highlight some of the challenges going forward. Themes include findings that ASD associated genes discovered by a variety of methods have been shown to contain disproportionate amounts of neurite outgrowth/cytoskeletal, synaptic, and more recently Wnt-related and chromatin modifying genes. Expression studies have highlighted a disproportionate expression of ASD gene sets during mid fetal cortical development, particularly for rare variants, with multiple analyses highlighting the striatum and cortical projection and interneurons as well. While these explorations have highlighted potentially interesting relationships among these ASD-related genes, there are challenges in how to best transition these insights into empirically testable hypotheses. Nonetheless, defining shared molecular or cellular pathology downstream of the diverse genes associated with ASDs could provide the cornerstones needed to build toward broadly applicable therapeutic approaches.
    Frontiers in Genetics 10/2015; 6. DOI:10.3389/fgene.2015.00301
  • Source
    • "Although a subset of ASD cases are now better understood, with their genetic contributions becoming more clear (Zhao et al. 2007; Betancur 2011; Iossifov et al. 2012, 2014; Bernier et al. 2014; Ronemus et al. 2014; Lyon and O'Rawe 2015), the large degree of phenotypic heterogeneity in ASDs leaves the vast majority of cases still poorly understood. Larger studies have focused on a subset of variant types, but here we have obtained a broader and more complete view of all the different types of genomic variation that could be contributing to the ASD phenotypes observed in this study. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Autism spectrum disorders (ASDs) are a group of developmental disabilities that affect social interaction and communication and are characterized by repetitive behaviors. There is now a large body of evidence that suggests a complex role of genetics in ASDs, in which many different loci are involved. Although many current population-scale genomic studies have been demonstrably fruitful, these studies generally focus on analyzing a limited part of the genome or use a limited set of bioinformatics tools. These limitations preclude the analysis of genome-wide perturbations that may contribute to the development and severity of ASD-related phenotypes. To overcome these limitations, we have developed and utilized an integrative clinical and bioinformatics pipeline for generating a more complete and reliable set of genomic variants for downstream analyses. Our study focuses on the analysis of three simplex autism families consisting of one affected child, unaffected parents, and one unaffected sibling. All members were clinically evaluated and widely phenotyped. Genotyping arrays and whole-genome sequencing were performed on each member, and the resulting sequencing data were analyzed using a variety of available bioinformatics tools. We searched for rare variants of putative functional impact that were found to be segregating according to de novo, autosomal recessive, X-linked, mitochondrial, and compound heterozygote transmission models. The resulting candidate variants included three small heterozygous copy-number variations (CNVs), a rare heterozygous de novo nonsense mutation in MYBBP1A located within exon 1, and a novel de novo missense variant in LAMB3. Our work demonstrates how more comprehensive analyses that include rich clinical data and whole-genome sequencing data can generate reliable results for use in downstream investigations.
Show more

Similar Publications


15 Reads
Available from