Article

Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
PLoS Genetics (Impact Factor: 8.17). 02/2012; 8(2):e1002521. DOI: 10.1371/journal.pgen.1002521
Source: PubMed

ABSTRACT 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.

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Available from: Martin Poot, Aug 29, 2015
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    • "Abbreviations: ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum disorder; FMR1, fragile X mental retardation ; FXS, fragile X syndrome; PON1, paraoxanase/arylesterase 1; PPI, protein–protein interaction; SLOS, Smith-Lemli-Opitz syn- drome ASD is likely a heterogeneous disorder with multiple causes, involving genes and the environment [8] [9] [10]. Numerous genetic studies of ASD have been conducted [11], supporting not only a strong genetic link in many cases, but also a high likely degree of heterogeneity of cause [12]. Many implicated genes are involved in nervous system development and neurotransmitter systems [13]. "
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    • "Since involvement of CNTN5 in ASD has been supported by both the CNV and the present candidate gene association study, further neurobiological and, in particular, neurobehavioral studies of this gene appear warranted [Poot, 2013]. It is conceivable that CNTN5 , in analogy to recently reported findings with SHANK2 in patients with ASD and ID [Leblond et al., 2012; Chilian et al., 2013], may be part of a gene interaction network consisting of physical interactions between the encoded proteins [Poot et al., 2011]. Alternatively, genes may form a network of epistatic regulation consisting of transcription factors and their cognate target sites. "
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    • "Some studies even question the possibility of any substantial impact of monogenic forms of ASD [97]. ASD is known to be a complex multifactorial disease [95-98,123] although several rare single-gene disorders with a high prevalence of ASD are known [38,113]. We speculate that the impact of synonymous variations/mutations is small but sufficient to produce phenotypic effects in synergy with the increasing neurotoxin load. "
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