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

• DOI: 10.1371/journal.pgen.1009679
• Publication Date: 2021-07-29T18:50:09Z
• Authors: Enrique Audain; Anna Wilsdon; Jeroen Breckpot; Jose M. G. Izarzu...; Tomas W. Fitzgerald; Anne-Karin Kahlert; Alejandro Sifrim; Florian Wünnemann; Yasset Perez-Riverol; Hashim Abdul-Khaliq; Mads Bak; Anne S. Bassett; Woodrow D. Benson; Felix Berger; Ingo Daehnert; Koenraad Devriendt; Sven Dittrich; Piers EF Daubeney; Vidu Garg; Karl Hackmann; Kirstin Hoff; Philipp Hofmann; Gregor Dombrowsky; Thomas Pickardt; Ulrike Bauer; Bernard D. Keavney; Sabine Klaassen; Hans-Heiner Kramer; Christian R. Mars...; Dianna M. Milewicz; Scott Lemaire; Joseph S. Coselli; Michael E. Mitchell; Aoy Tomita-Mitchell; Siddharth K. Prakash; Karl Stamm; Alexandre F. R. S...; Candice K. Silver...; Reiner Siebert; Brigitte Stiller; Jill A. Rosenfeld; Inga Vater; Alex V. Postma; Almuth Caliebe; J. David Brook; Gregor Andelfinger; Matthew E. Hurles; Bernard Thienpont; Lars Allan Larsen; Marc-Phillip Hitz
• Keywords: Haploinsufficiency; Candidate gene

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 DNVs identified probands with including cases sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 14,082 controls gene-wise burden deletions versus controls. In addition, rate testing 2,489 parent-offspring trios. Our revealed 21 genes which were significantly affected by and/or probands. Fourteen these previously been associated while remaining (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B WHSC1) only small series or show new associations CHD. systems level protein-protein interaction networks involved Notch signaling pathway, heart morphogenesis, DNA repair cilia/centrosome function. Taken together, this approach highlights importance re-analyzing existing datasets to strengthen association pathways.