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: 2.84). 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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    • "The genetics of ASD is complex with involvement of both rare and common genetic variants. Rare genetic variants predisposing to ASD are currently thought to account for 10–20 % of all ASD cases (Betancur 2011). "
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    ABSTRACT: Children with an autism spectrum disorder (ASD) and their unaffected siblings from 54 simplex (SPX, one individual in the family affected) and 59 multiplex (MPX, two or more individuals affected) families, and 124 controls were assessed on intelligence, social cognition and executive functions. SPX and MPX ASD probands displayed similar cognitive profiles, but within-family contrasts were highest in SPX families, suggesting SPX-MPX stratification may help parse etiological heterogeneity of ASD. Unaffected siblings (regardless SPX or MPX) were mostly unimpaired, suggesting that cognitive problems may be part of the defining features of ASD, rather than being an endophenotypic trait. Except for affective prosody, which appeared to be the most sensitive cognitive marker for detecting familial risk for ASD.
    Journal of Autism and Developmental Disorders 09/2015; DOI:10.1007/s10803-015-2572-9 · 3.06 Impact Factor
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    • "Despite many years of scientific interest, the molecular and neurobiological bases of the disorder are still far from clear. This is mainly due to the polygenic (over a hundred contributing genes) character of the disorder (Betancur, 2011; Geschwind, 2011). With only 10–15% of cases associated with monogenic disorders such as Fragile X mental retardation syndrome (FXS), Rett's syndrome (RTT) or tuberous sclerosis complex (TSC), the search for biological markers of relevant behavioral impairments relies heavily on validation of idiopathic models of the disorder. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized, in part, by an inability to adequately respond to social cues. Patients diagnosed with ASD are often devoid of empathy and impaired in understanding other people's emotional perspective. The neuronal correlates of this impairment are not fully understood. Replicating such a behavioral phenotype in a mouse model of autism would allow us insight into the neuronal background of the problem. Here we tested BTBR T(+)Itpr3(tf)/J (BTBR) and c57BL/6J (B6) mice in two behavioral paradigms: the Transfer of Emotional Information test and the Social Proximity test. In both tests BTBR mice displayed asocial behavior. We analyzed c-Fos protein expression in several brain regions after each of these tests, and found that, unlike B6 mice, BTBR mice react to a stressed cagemate exposure in the Transfer of Emotional Information test with no increase of c-Fos expression in either the prefrontal cortex or the amygdala. However, after Social Proximity exposure we observed a strong increase in c-Fos expression in the CA3 field of the hippocampus and two hypothalamic regions of BTBR brains. This response was accompanied by a strong activation of periaqueductal regions related to defensiveness, which suggests that BTBR mice find unavoidable social interaction highly aversive.
    Frontiers in Behavioral Neuroscience 08/2015; 9:199. DOI:10.3389/fnbeh.2015.00199 · 3.27 Impact Factor
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    • "Intellectual disability (ID) is a frequent comorbidity of ASD, present in more than half of ASD subjects (Srivastava and Schwartz 2014; Tuchman and Rapin 2002; Amiet et al. 2008). ASD are highly genetically determined, but the genetic factors involved in these disorders are extremely heterogeneous and have proven difficult to identify (Betancur 2011; Huguet et al. 2013; Jeste and Geschwind 2014), and, in spite of the acceleration of gene identification due to technological advances, a genetic cause is still found in a minority of ASD cases. De novo or inherited copy number variants (CNV), strongly associated with autism and probably conferring high susceptibility to ASD, have been identified in 2–10 % of patients (Girirajan et al. 2013; Sanders et al. 2011; Glessner et al. 2009; Bucan et al. 2009; Pinto et al. 2010; Huguet et al. 2013). "
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    ABSTRACT: Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.
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