Functional Impact of Global Rare Copy Number Variation in Autism Spectrum Disorder

By D. Pinto, A. Pagnamenta, L. Klei, R. Anney, Daniele Merico, R. Regan, J. Conroy, Tiago R. Magalhães, C. Correia, B. Abrahams and 167 more. Nature, 2010

2,055 citations recorded by the source corpus.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable (∼90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6fcc772f3e9ebb4bb90eba6fe78c01bffd29fcd1

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Citations in the corpus

Synaptic, transcriptional, and chromatin genes disrupted in autism (2014, neutral): “Three critical pathways for typical development are damaged by risk variation: (1) chromatin remodeling, (2) transcription and splicing, and, (3) synaptic function.”
SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs) (2013, neutral): “Letter to the Editor Previous work has crafted curated lists of genes implicated in autism spectrum disorders (ASDs) [1-5], and in some cases developed loosely defined “evidence scores” for entries [6-8].”
Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2 (2012, background): “96; 1/1: 504 events, n (N) 5 12 (4); 2/2: 630 events, n 5 15 (5)).”
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders (2014, methodology): “The second phase was divided in two stages; the results of stage 1, involving the first half of the families, were published in 2010.(6,20) In stage 2, we genotyped the remaining families (n 1⁄4 1,604) for a total of over 2,845 families and performed genomewide CNV (this study) and association studi”
Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants (2011, methodology): “and analysis of data from genome-wide association studie”
BioPAX – A community standard for pathway data sharing (2010, neutral): “A number of recent papers have used this pathway analysis workflow to highlight genes and pathways that are active in specific model organisms or diseased tissues, such as breast cancer, using gene and protein expression, copy number variants and single-nucleotide polymorphisms 19,44–49 .”
Autism risk factors: genes, environment, and gene-environment interactions (2012, background): “This model is supported by the observation that all recurrent genetic defects reported in autism, including autism without mental retardation, have been causally implicated in intellectual disability,(56) and that analysis of the genes affected by rare CNVs reveal that they are strongly functionally”
Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. (2011, background): “…(Lynch et al., 2009), MED12 mutation, Lujan‐Fryns syndrome (Schwartz et al., 2007), 22q11 deletion syndrome/DiGeorge syndrome (Gothelf et al., 2004; Pinto et al., 2010), TBX1 mutation, 22q11 deletion syndrome phenotype (Paylor et al., 2006), NLGN3 mutation (Jamain et al., 2003), NLGN4X…”
Rare de novo and transmitted copy-number variation in autistic spectrum disorders. (2011, neutral): “’’ These observations are derived from both this study and the previous literature (Marshall et al., 2008; Pinto et al., 2010; Sebat et al., 2007; Zhao et al., 2007).”