Dataset Information

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

ABSTRACT: 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.

SUBMITTER: Sanders SJ

PROVIDER: S-EPMC3939065 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Publications

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

Sanders Stephan J SJ Ercan-Sencicek A Gulhan AG Hus Vanessa V Luo Rui R Murtha Michael T MT Moreno-De-Luca Daniel D Chu Su H SH Moreau Michael P MP Gupta Abha R AR Thomson Susanne A SA Mason Christopher E CE Bilguvar Kaya K Celestino-Soper Patricia B S PB Choi Murim M Crawford Emily L EL Davis Lea L Wright Nicole R Davis NR Dhodapkar Rahul M RM DiCola Michael M DiLullo Nicholas M NM Fernandez Thomas V TV Fielding-Singh Vikram V Fishman Daniel O DO Frahm Stephanie S Garagaloyan Rouben R Goh Gerald S GS Kammela Sindhuja S Klei Lambertus L Lowe Jennifer K JK Lund Sabata C SC McGrew Anna D AD Meyer Kyle A KA Moffat William J WJ Murdoch John D JD O'Roak Brian J BJ Ober Gordon T GT Pottenger Rebecca S RS Raubeson Melanie J MJ Song Youeun Y Wang Qi Q Yaspan Brian L BL Yu Timothy W TW Yurkiewicz Ilana R IR Beaudet Arthur L AL Cantor Rita M RM Curland Martin M Grice Dorothy E DE Günel Murat M Lifton Richard P RP Mane Shrikant M SM Martin Donna M DM Shaw Chad A CA Sheldon Michael M Tischfield Jay A JA Walsh Christopher A CA Morrow Eric M EM Ledbetter David H DH Fombonne Eric E Lord Catherine C Martin Christa Lese CL Brooks Andrew I AI Sutcliffe James S JS Cook Edwin H EH Geschwind Daniel D Roeder Kathryn K Devlin Bernie B State Matthew W MW

Neuron 20110601 5

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 ...[more]

PMID: 21658581

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Project description:Autism spectrum disorders (ASDs) are highly heritable and characterised by deficits in social interaction and communication, as well as restricted and repetitive behaviours. Although a number of highly penetrant ASD gene variants have been identified, there is growing evidence to support a causal role for combinatorial effects arising from the contributions of multiple loci. By examining synaptic and circadian neurological phenotypes resulting from the dosage variants of unique human:fly orthologues in Drosophila, we observe numerous synergistic interactions between pairs of informatically-identified candidate genes whose orthologues are jointly affected by large de novo copy number variants (CNVs). These CNVs were found in the genomes of individuals with autism, including a patient carrying a 22q11.2 deletion. We first demonstrate that dosage alterations of the unique Drosophila orthologues of candidate genes from de novo CNVs that harbour only a single candidate gene display neurological defects similar to those previously reported in Drosophila models of ASD-associated variants. We then considered pairwise dosage changes within the set of orthologues of candidate genes that were affected by the same single human de novo CNV. For three of four CNVs with complete orthologous relationships, we observed significant synergistic effects following the simultaneous dosage change of gene pairs drawn from a single CNV. The phenotypic variation observed at the Drosophila synapse that results from these interacting genetic variants supports a concordant phenotypic outcome across all interacting gene pairs following the direction of human gene copy number change. We observe both specificity and transitivity between interactors, both within and between CNV candidate gene sets, supporting shared and distinct genetic aetiologies. We then show that different interactions affect divergent synaptic processes, demonstrating distinct molecular aetiologies. Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease.

Dataset Information

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

Publications

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism.

Similar Datasets

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