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Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

PLoS genetics | May 18, 2012

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Pubmed ID: 22346768 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Adult | Alternative Splicing | Cell Line | Child | Child Development Disorders, Pervasive | Child, Preschool | Female | Gene Dosage | Gene Expression Regulation | Humans | Male | Nerve Tissue Proteins | Neurons | Protein Isoforms | RNA Splice Sites | Receptors, Nicotinic | Sequence Deletion | Synapses | Tissue Distribution | alpha7 Nicotinic Acetylcholine Receptor

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Database of Genomic Variants: A curated catalogue of structural variation in the human genome

A curated catalogue of human genomic structural variation identified in healthy control samples for studies aiming to correlate genomic variation with phenotypic data. Structural variation is defined as genomic alterations that involve segments of DNA that are larger than 50bp. It is continuously updated with new data from peer reviewed research studies. The Database is no longer accepting direct submission of data as they are currently part of a collaboration with two new archival CNV databases at EBI and NCBI, called DGVa and dbVAR, respectively. One of the changes to DGV as part of this collaborative effort is that they will no longer be accepting direct submissions, but rather obtain the datasets from DGVa (short for DGV archive). This will ensure that the three databases are synchronized, and will allow for an official accessioning of variants.


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Software application that is an interactive graphic interface to visualise results from whole genome genotyping. It allows one to visualise single subjects and groups of subjects, and provides a direct connection with the UCSC Genome Browser. (entry from Genetic Analysis Software)


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