Rare De Novo Variants Associated with Autism Implicate a Large Functional Network of Genes Involved in Formation and Function of Synapses

Center for Computational Biology and Bioinformatics and Department of Biomedical Informatics, Columbia University, 1130 St. Nicolas Ave, New York, NY 10032, USA.
Neuron (Impact Factor: 15.05). 06/2011; 70(5):898-907. DOI: 10.1016/j.neuron.2011.05.021
Source: PubMed

ABSTRACT Identification of complex molecular networks underlying common human phenotypes is a major challenge of modern genetics. In this study, we develop a method for network-based analysis of genetic associations (NETBAG). We use NETBAG to identify a large biological network of genes affected by rare de novo CNVs in autism. The genes forming the network are primarily related to synapse development, axon targeting, and neuron motility. The identified network is strongly related to genes previously implicated in autism and intellectual disability phenotypes. Our results are also consistent with the hypothesis that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males. Overall, the presented analysis of de novo variants supports the hypothesis that perturbed synaptogenesis is at the heart of autism. More generally, our study provides proof of the principle that networks underlying complex human phenotypes can be identified by a network-based functional analysis of rare genetic variants.

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    • "More recently, exome sequencing of parent– offspring trios has shown that de novo point mutations contribute to ASD in 10–30 % of sporadic patients (Murdoch and State 2013; Krumm et al. 2014; O'Roak et al. 2011, 2012; Sanders et al. 2012; Neale et al. 2012; Iossifov et al. 2012, 2014). These studies predicted that ASD could result from genetic abnormalities in several hundreds of different genes, many of which are, nonetheless, interconnected or part of common functional pathways (Neale et al. 2012; O'Roak et al. 2012; Sanders et al. 2012; Iossifov et al. 2012; Gilman et al. 2011). Examples of pathways repeatedly involved in ASD include: synaptic function, illustrated by mutations in SHANK1-3 scaffolding proteins, neuroligins , neurexins, contactins and contactin-associated proteins encoding genes; the mTOR pathway, illustrated by mutations in TSC1/TSC2 or PTEN that cause syndromic forms of ASD; chromatin remodeling; and Wnt signaling (Krumm et al. 2014; Jeste and Geschwind 2014; 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.
    Amino Acids 07/2015; DOI:10.1007/s00726-015-2057-3 · 3.29 Impact Factor
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    • "proteins (Chatr-Aryamontri et al., 2013; Corominas et al., 2014; Rolland et al., 2014). Until now, most protein-protein interaction (PPI) studies of CNVs in psychiatric disorders have been focused on analyzing static topological network properties such as connectivity, modules , and clusters (Gilman et al., 2011; Noh et al., 2013; Pinto et al., 2010). However, cells are highly dynamic entities, and protein interactions could be profoundly influenced by spatial and temporal availability of the interacting gene products, as demonstrated previously for yeast grown under varying experimental conditions (de Lichtenberg et al., 2005; Luscombe et al., 2004). "
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    ABSTRACT: The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 02/2015; 85(4):742-54. DOI:10.1016/j.neuron.2015.01.010 · 15.05 Impact Factor
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    • "bands carry more and larger de novo CNVs than male probands, suggesting there is a protective mechanism for female to buffer the harmful genetic mutations. Furthermore, Network analysis highlighted genes set involved synaptogenesis, axon guidance and neuronal motility [65]. Finally, we summarized the most frequent CNVs in Table 1 and Fig. 1. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. The past decade has witnessed tremendous progress in the genetic studies of ASD. In this article, we review the accumulating literatures on the monogenic forms of ASD and chromosomal abnormalities associated with ASD, the genome-wide linkage and association studies, the copy number variation (CNV) and the next generation sequencing (NGS) studies. With more than hundreds of mutations being implicated, the convergent biological pathways are emerging and the genetic landscape of ASD becomes clearer. The genetic studies provide a solid basis for future translational study for better diagnoses, intervention and treatment of ASD.
    Biochemical and Biophysical Research Communications 09/2014; 452(2). DOI:10.1016/j.bbrc.2014.08.108 · 2.30 Impact Factor
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