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      The emerging picture of autism spectrum disorder: genetics and pathology.

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          Abstract

          Autism spectrum disorder (ASD) is defined by impaired social interaction and communication accompanied by stereotyped behaviors and restricted interests. Although ASD is common, its genetic and clinical features are highly heterogeneous. A number of recent breakthroughs have dramatically advanced our understanding of ASD from the standpoint of human genetics and neuropathology. These studies highlight the period of fetal development and the processes of chromatin structure, synaptic function, and neuron-glial signaling. The initial efforts to systematically integrate findings of multiple levels of genomic data and studies of mouse models have yielded new clues regarding ASD pathophysiology. This early work points to an emerging convergence of disease mechanisms in this complex and etiologically heterogeneous disorder.

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          Most cited references 246

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          Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

          It is well established that autism spectrum disorders (ASD) have a strong genetic component. However, for at least 70% of cases, the underlying genetic cause is unknown 1 . Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes—so-called sporadic or simplex families 2,3 , we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported 4 . Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19) 4 , for a total of 677 individual exomes from 209 families. Here we show de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD 5 . Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes, CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3, and SCN1A. Combined with copy number variant (CNV) data, these results suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics.
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            Strong association of de novo copy number mutations with autism.

            We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
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              Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

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                Author and article information

                Journal
                Annu Rev Pathol
                Annual review of pathology
                1553-4014
                1553-4006
                2015
                : 10
                Affiliations
                [1 ] Interdepartmental Program in Bioinformatics.
                Article
                10.1146/annurev-pathol-012414-040405
                25621659

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