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| Item Type: | Article | ||||
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| Title: | Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease | ||||
| Creators Name: | Audain, E. and Wilsdon, A. and Breckpot, J. and Izarzugaza, J.M. and Fitzgerald, T.W. and Kahlert, A.K. and Sifrim, A. and Wünnemann, F. and Perez-Riverol, Y. and Abdul-Khaliq, H. and Bak, M. and Bassett, A.S. and Benson, W.D. and Berger, F. and Daehnert, I. and Devriendt, K. and Dittrich, S. and Daubeney, P.E. and Garg, V. and Hackmann, K. and Hoff, K. and Hofmann, P. and Dombrowsky, G. and Pickardt, T. and Bauer, U. and Keavney, B.D. and Klaassen, S. and Kramer, H.H. and Marshall, C.R. and Milewicz, D.M. and Lemaire, S. and Coselli, J.S. and Mitchell, M.E. and Tomita-Mitchell, A. and Prakash, S.K. and Stamm, K. and Stewart, A.F.R. and Silversides, C.K. and Siebert, R. and Stiller, B. and Rosenfeld, J.A. and Vater, I. and Postma, A.V. and Caliebe, A. and Brook, J.D. and Andelfinger, G. and Hurles, M.E. and Thienpont, B. and Larsen, L.A. and Hitz, M.P. | ||||
| Abstract: | Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways. | ||||
| Keywords: | DNA Copy Number Variations, Genetic Databases, Gene Expression, Gene Expression Profiling, Genetic Predisposition to Disease, Genomics, Haploinsufficiency, Congenital Heart Defects, Ion Channels, Membrane Proteins, Single Nucleotide Polymorphism, Transcriptome / Genetics | ||||
| Source: | PLoS Genetics | ||||
| ISSN: | 1553-7404 | ||||
| Publisher: | Public Library of Science | ||||
| Volume: | 17 | ||||
| Number: | 7 | ||||
| Page Range: | e1009679 | ||||
| Date: | 29 July 2021 | ||||
| Additional Information: | Erratum in: Nat PLoS Genet 17(9): e1009809. | ||||
| Official Publication: | https://doi.org/10.1371/journal.pgen.1009679 | ||||
| PubMed: | View item in PubMed | ||||
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