TY - JOUR
T1 - Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease
AU - Audain, Enrique
AU - Wilsdon, Anna
AU - Breckpot, Jeroen
AU - Izarzugaza, Jose M G
AU - Fitzgerald, Tomas W
AU - Kahlert, Anne-Karin
AU - Sifrim, Alejandro
AU - Wünnemann, Florian
AU - Perez-Riverol, Yasset
AU - Abdul-Khaliq, Hashim
AU - Bak, Mads
AU - Bassett, Anne S
AU - Benson, D Woodrow
AU - Berger, Felix
AU - Daehnert, Ingo
AU - Devriendt, Koenraad
AU - Dittrich, Sven
AU - Daubeney, Piers Ef
AU - Garg, Vidu
AU - Hackmann, Karl
AU - Hoff, Kirstin
AU - Hofmann, Philipp
AU - Dombrowsky, Gregor
AU - Pickardt, Thomas
AU - Bauer, Ulrike
AU - Keavney, Bernard D
AU - Klaassen, Sabine
AU - Kramer, Hans-Heiner
AU - Marshall, Christian R
AU - Milewicz, Dianna M
AU - Lemaire, Scott
AU - Coselli, Joseph S
AU - Mitchell, Michael E
AU - Tomita-Mitchell, Aoy
AU - Prakash, Siddharth K
AU - Stamm, Karl
AU - Stewart, Alexandre F R
AU - Silversides, Candice K
AU - Siebert, Reiner
AU - Stiller, Brigitte
AU - Rosenfeld, Jill A
AU - Vater, Inga
AU - Postma, Alex V
AU - Caliebe, Almuth
AU - Brook, J David
AU - Andelfinger, Gregor
AU - Hurles, Matthew E
AU - Thienpont, Bernard
AU - Larsen, Lars Allan
AU - Hitz, Marc-Phillip
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - DNA Copy Number Variations/genetics
KW - Databases, Genetic
KW - Gene Expression/genetics
KW - Gene Expression Profiling/methods
KW - Genetic Predisposition to Disease/genetics
KW - Genomics/methods
KW - Haploinsufficiency/genetics
KW - Heart Defects, Congenital/genetics
KW - Humans
KW - Ion Channels/genetics
KW - Membrane Proteins/genetics
KW - Polymorphism, Single Nucleotide/genetics
KW - Transcriptome/genetics
U2 - 10.1371/journal.pgen.1009679
DO - 10.1371/journal.pgen.1009679
M3 - Article
C2 - 34324492
SN - 1553-7390
VL - 17
SP - e1009679
JO - PLoS Genetics
JF - PLoS Genetics
IS - 7
ER -
