1. Indexing Effects of Copy Number Variation on Genes Involved in Developmental Delay
- Author
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Stephen W. Scherer, Bhooma Thiruvahindrapuram, Ann M. Joseph-George, Peter Kannu, Emmanuelle Lemyre, Ada Chan, Susan Walker, Mary Shago, Grace Yoon, Janet A. Buchanan, Abdul Noor, Lia D’Abate, Christian R. Marshall, Melissa T. Carter, Sonia Nizard, Mehdi Zarrei, Géraldine Mathonnet, Kristiina Tammimies, Thomas Nalpathamkalam, Ryan K. C. Yuen, Mohammed Uddin, Frédérique Tihy, Daniele Merico, Dimitri J. Stavropoulos, Giovanna Pellecchia, Matthew J. Gazzellone, Erik C. Thorland, Koenraad Devriendt, and Marsha Speevak
- Subjects
Adult ,Male ,Proteomics ,0301 basic medicine ,Candidate gene ,DNA Copy Number Variations ,Developmental Disabilities ,Cell Cycle Proteins ,Genome-wide association study ,Biology ,Gene dosage ,Article ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Child ,Gene ,Adaptor Proteins, Signal Transducing ,Genetics ,Regulation of gene expression ,Multidisciplinary ,Gene Expression Profiling ,Brain ,Gene Expression Regulation, Developmental ,Gene expression profiling ,030104 developmental biology ,Female ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P −15) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P −50, OR = 2.11) and adult (P −18, OR = 1.55) tissues. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or as variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs.
- Published
- 2016