Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting

INSERM, U952, Université Pierre et Marie Curie, Paris, France.
Brain research (Impact Factor: 2.83). 12/2010; 1380:42-77. DOI: 10.1016/j.brainres.2010.11.078
Source: PubMed

ABSTRACT 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.

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    • "[16]. Over 100 genes and 40 genomic loci appear to be associated [17] [18]. A recent study described the first clear link in ASD subtypes and the CHD8 gene mutation [19], indicating that more progress may follow in the genetic understanding of other subtypes of ASD. "
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    ABSTRACT: Current directions in autism spectrum disorder (ASD) research may require moving beyond genetic analysis alone, based on the complexity of the disorder, heterogeneity and convergence of genetic alterations at the cellular/functional level. Mass spectrometry (MS) has been increasingly used to study central nervous system (CNS) disorders, including ASDs. Proteomic research using MS is directed at understanding endogenous protein changes that occur in ASD. This review focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using MS, including fragile X syndrome (FXS) and Smith-Lemli-Opitz Syndrome (SLOS), genetic syndromes highly associated with ASD comorbidity.This article is protected by copyright. All rights reserved
    PROTEOMICS - CLINICAL APPLICATIONS 02/2015; 9(1-2). DOI:10.1002/prca.201400116 · 2.68 Impact Factor
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    • "Autism spectrum disorders (ASD) are characterized by pervasive impairments in the domains of socialcommunicative skills and restricted/repetitive behavior (APA, 2000). Heterogeneity in ASD constitutes a challenge to understanding the etiology of the disorder (Jones and Klin, 2009; Betancur, 2011; Pelphrey et al., 2011). For example , deficits in theory of mind, or mentalizing – making inferences about others' minds – are widespread in ASD (Baron-Cohen, 2001). "
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    ABSTRACT: Posterior superior temporal sulcus (pSTS) is specialized for interpreting perceived human actions, and disruptions to its function occur in autism spectrum disorder (ASD). Here we consider the role of Crus I of neocerebellum in supporting pSTS function. Research has associated Crus I activity with imitation and biological motion perception, and neocerebellum is theorized to coordinate activity among cerebral sites more generally. Moreover, cerebellar abnormalities have been associated with ASD. We hypothesized that disordered Crus I–pSTS interactions could predict social deficits in ASD. 15 high functioning adolescents with ASD and 15 same-age comparison youth participated in an fMRI imitation paradigm; ratings of mentalizing ability were collected via parent report. We predicted that stronger Crus I–pSTS interactions would be associated with better mentalizing ability. Consistent with these hypotheses, stronger psychophysiological interactions between Crus I and right pSTS were associated with greater mentalizing ability among adolescents with ASD. Whole-brain analyses also indicated that typically developing youth recruited right inferior frontal gyrus, left pSTS, medial occipital regions, and precuneus more strongly during imitation than did youth with ASD. Overall, these results indicate that variability in neocerebellar interactions with key cortical social brain sites may help explain individual differences in social perceptual outcomes in ASD.
    Developmental Cognitive Neuroscience 10/2014; 10. DOI:10.1016/j.dcn.2014.08.001 · 3.71 Impact Factor
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    • "The genetic etiology of ASD is no less varied. More than 100 genes and genomic regions have been associated with ASD (Betancur, 2011), and >800 genes have been suggested to play a role in Cell 158, 1–14, July 17, 2014 ª2014 Elsevier Inc. 1 ASD (Iossifov et al., 2012; Neale et al., 2012; O'Roak et al., 2012b; Sanders et al., 2012). Given that parsing the behavioral heterogeneity has yielded limited utility, genetically defined subtypes may prove more beneficial in illuminating molecular mechanisms underlying ASD, the course and prognosis of a subgroup of individuals with ASD, and individualized treatment targets. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behav-iorally have met with limited success. Hypothesiz-ing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 un-affected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 muta-tions, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitu-lates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointes-tinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disrup-tions define a distinct ASD subtype and reveal unex-pected comorbidities between brain development and enteric innervation. INTRODUCTION
    Cell 06/2014; 158(2). DOI:10.1016/j.cell.2014.06.017 · 33.12 Impact Factor
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