Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

Program on Neurogenetics, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA.
Neuron (Impact Factor: 15.05). 06/2011; 70(5):863-85. DOI: 10.1016/j.neuron.2011.05.002
Source: PubMed


We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

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    • "or duplications that cause WBS duplication syndrome (OMIM#609757) (Depienne et al. 2007; Merla et al. 2010; Sanders et al. 2011; Somerville et al. 2005; Torniero et al. 2007; Van der Aa et al. 2009). Patients with WBS duplication syndrome have only recently been described and little mapping data exists that can discriminate the individual genetic contribution to the phenotypes but in WBS, a series of atypical deletion patients indicate that loss of GTF2IRD1 and/or GTF2I is necessary to manifest the craniofacial abnormalities , mental retardation, visuospatial construction deficits and hypersociability of WBS (Antonell et al. 2010). "
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    ABSTRACT: GTF2IRD1 is one of the three members of the GTF2I gene family, clustered on chromosome 7 within a 1.8 Mb region that is prone to duplications and deletions in humans. Hemizygous deletions cause Williams-Beuren syndrome (WBS) and duplications cause WBS duplication syndrome. These copy number variations disturb a variety of developmental systems and neurological functions. Human mapping data and analyses of knockout mice show that GTF2IRD1 and GTF2I underpin the craniofacial abnormalities, mental retardation, visuospatial deficits and hypersociability of WBS. However, the cellular role of the GTF2IRD1 protein is poorly understood due to its very low abundance and a paucity of reagents. Here, for the first time, we show that endogenous GTF2IRD1 has a punctate pattern in the nuclei of cultured human cell lines and neurons. To probe the functional relationships of GTF2IRD1 in an unbiased manner, yeast two-hybrid libraries were screened, isolating 38 novel interaction partners, which were validated in mammalian cell lines. These relationships illustrate GTF2IRD1 function, as the isolated partners are mostly involved in chromatin modification and transcriptional regulation, whilst others indicate an unexpected role in connection with the primary cilium. Mapping of the sites of protein interaction also indicates key features regarding the evolution of the GTF2IRD1 protein. These data provide a visual and molecular basis for GTF2IRD1 nuclear function that will lead to an understanding of its role in brain, behaviour and human disease.
    Full-text · Article · Aug 2015 · Human Genetics
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    • "These findings demonstrate diverging mechanisms by which reverse transport of DA can be disrupted. They align with other examples of neurodevelopmental risk emerging from genetic variants causing opposite effects on gene expression or signaling cascades (Sanders et al., 2011; Cook et al., 1997). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. "
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    ABSTRACT: Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.
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    • "It should be noted, however, that DECIPHER lists disruptions and heterozygous losses of CNTNAP2, which have been inherited from healthy parents ( fig. 2 , red-framed bars) [Bragin et al., 2014]. While the Database of Genomic Variants [MacDonald et al., 2013] lists a number of phenotypically neutral CNVs within CNTNAP2 , the burden of CNVs in CNTNAP2 is not elevated in individuals with ID and autism [Cooper et al., 2011; Sanders et al., 2011]. Also, 2 ASD patients had small proximal losses in CNTNAP2 , which they inherited from their healthy mothers [Gregor et al., 2011]. "
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    ABSTRACT: Based on genomic rearrangements and copy number variations the contactin associated protein 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome (GTS) , intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt Hopkins syndrome, and attention span / hyperactivity disorder (ADHD). To explain the phenotypic pleiotropy of CNTNAP2 alterations several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein, which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers less than 0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.
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