Article

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

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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    • "There more than 1000 genes that are predicted to play a role in ASD. In an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD, the recent exhaustive review of the clinical genetics and research genetics literature has shown that there may be 103 disease genes and 44 genomic loci reported in subjects with ASD or autistic behavior (Betancur, 2011;Tammimies et al., 2015). These genes and loci have all been causally implicated in intellectual disability, indicating that these two neurodevelopmental disorders share common genetic bases. "
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    ABSTRACT: Autism spectrum disorders (ASD) are highly heterogeneous developmental conditions characterized by deficits in social interaction, verbal and nonverbal communication, and obsessive/stereotyped patterns of behavior and repetitive movements. Social interaction impairments are the most characteristic deficits in ASD. There is also evidence of impoverished language and empathy, a profound inability to use standard nonverbal behaviors (eye contact, affective expression) to regulate social interactions with others, difficulties in showing empathy, failure to share enjoyment, interests and achievements with others, and a lack of social and emotional reciprocity. In developed countries, it is now reported that 1%–1.5% of children have ASD, and in the US 2015 CDC reports that approximately one in 45 children suffer from ASD. Despite the intense research focus on ASD in the last decade, the underlying etiology remains unknown. Genetic research involving twins and family studies strongly supports a significant contribution of environmental factors in addition to genetic factors in ASD etiology. A comprehensive literature search has implicated several environmental factors associated with the development of ASD. These include pesticides, phthalates, polychlorinated biphenyls, solvents, air pollutants, fragrances, glyphosate and heavy metals, especially aluminum used in vaccines as adjuvant. Importantly, the majority of these toxicants are some of the most common ingredients in cosmetics and herbicides to which almost all of us are regularly exposed to in the form of fragrances, face makeup, cologne, air fresheners, food flavors, detergents, insecticides and herbicides. In this review we describe various scientific data to show the role of environmental factors in ASD.
    Full-text · Article · Mar 2016 · Environment International
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    • "We performed ultradeep sequencing on DNA from postmortem cerebral cortical and/or cerebellar brain samples from 55 ASD cases, 50 neurotypical controls, and 17 cases with suspected ASD or related diagnoses (Figure 1A; see Table S1 available online ). In order to achieve the high coverage necessary to sensitively detect somatic mosaic mutations, we used a targeted panel of 78 ASD candidate genes showing dominant or X-linked inheritance (see Supplemental Experimental Procedures) (Basu et al., 2009; Betancur, 2011; O'Roak et al., 2012). We achieved 5473 average coverage, with 95.7% of the analyzable target regions covered by R100 reads and 48.2% covered by R1,000 reads, providing sensitivity to detect somatic mutations in these genes to a level of z5% alternate allele frequency (AAF). "
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    ABSTRACT: Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.
    Full-text · Article · Dec 2015 · Neuron
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    • "Many persons with ASD also experience heightened or reduced sensitivity to sensory stimuli such as sound and temperature. Approximately 90% of autism cases are classified as idiopathic while about 10% are caused by known gene mutations (Betancur, 2011; Zafeiriou et al., 2013). The genetic forms of ASD are widely studied in humans and animal models in part because knowledge obtained may prove valuable for enhancing our understanding of idiopathic autism. "
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    ABSTRACT: The cerebellum contains the largest number of neurons and synapses of any structure in the central nervous system. The concept that the cerebellum is solely involved in fine motor function has become outdated; substantial evidence has accumulated linking the cerebellum with higher cognitive functions including language. Cerebellar deficits have been implicated in autism for more than two decades. The computational power of the cerebellum is essential for many, if not most of the processes that are perturbed in autism including language and communication, social interactions, stereotyped behavior, motor activity and motor coordination, and higher cognitive functions. The link between autism and cerebellar dysfunction should not be surprising to those who study its cellular, physiological, and functional properties. Postmortem studies have revealed neuropathological abnormalities in cerebellar cellular architecture while studies on mouse lines with cell loss or mutations in single genes restricted to cerebellar Purkinje cells have also strongly implicated this brain structure in contributing to the autistic phenotype. This connection has been further substantiated by studies investigating brain damage in humans restricted to the cerebellum. In this review, we summarize advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders.
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