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Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

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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.G. 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 Belmont, J.W. and Benson, D.W. and Berger, F. and Daehnert, I. and Devriendt, K. and Dittrich, S. and Daubeney, P. 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.A. and Coselli, J. 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:Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). 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 mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations 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 singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting 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.
Keywords:Congenital Heart Disease, Copy Number Variants, De novo Mutations
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.06.25.169573
Date:25 June 2020
Official Publication:https://doi.org/10.1101/2020.06.25.169573
Related to:
https://edoc.mdc-berlin.de/20796/Final version

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