Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.
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...
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2021
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oai:doaj.org-article:92067f3613e64d39b29f8fdaa8154ba82021-12-02T20:02:54ZIntegrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.1553-73901553-740410.1371/journal.pgen.1009679https://doaj.org/article/92067f3613e64d39b29f8fdaa8154ba82021-07-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009679https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Numerous 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.Enrique AudainAnna WilsdonJeroen BreckpotJose M G IzarzugazaTomas W FitzgeraldAnne-Karin KahlertAlejandro SifrimFlorian WünnemannYasset Perez-RiverolHashim Abdul-KhaliqMads BakAnne S BassettD Woodrow BensonFelix BergerIngo DaehnertKoenraad DevriendtSven DittrichPiers Ef DaubeneyVidu GargKarl HackmannKirstin HoffPhilipp HofmannGregor DombrowskyThomas PickardtUlrike BauerBernard D KeavneySabine KlaassenHans-Heiner KramerChristian R MarshallDianna M MilewiczScott LemaireJoseph S CoselliMichael E MitchellAoy Tomita-MitchellSiddharth K PrakashKarl StammAlexandre F R StewartCandice K SilversidesReiner SiebertBrigitte StillerJill A RosenfeldInga VaterAlex V PostmaAlmuth CaliebeJ David BrookGregor AndelfingerMatthew E HurlesBernard ThienpontLars Allan LarsenMarc-Phillip HitzPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 7, p e1009679 (2021) |
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Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Enrique Audain Anna Wilsdon Jeroen Breckpot Jose M G Izarzugaza Tomas W Fitzgerald Anne-Karin Kahlert Alejandro Sifrim Florian Wünnemann Yasset Perez-Riverol Hashim Abdul-Khaliq Mads Bak Anne S Bassett D Woodrow 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 Marshall Dianna M Milewicz Scott Lemaire Joseph S Coselli Michael E Mitchell Aoy Tomita-Mitchell Siddharth K Prakash Karl Stamm Alexandre F R Stewart Candice K Silversides 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 Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| description |
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. |
| format |
article |
| author |
Enrique Audain Anna Wilsdon Jeroen Breckpot Jose M G Izarzugaza Tomas W Fitzgerald Anne-Karin Kahlert Alejandro Sifrim Florian Wünnemann Yasset Perez-Riverol Hashim Abdul-Khaliq Mads Bak Anne S Bassett D Woodrow 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 Marshall Dianna M Milewicz Scott Lemaire Joseph S Coselli Michael E Mitchell Aoy Tomita-Mitchell Siddharth K Prakash Karl Stamm Alexandre F R Stewart Candice K Silversides 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 |
| author_facet |
Enrique Audain Anna Wilsdon Jeroen Breckpot Jose M G Izarzugaza Tomas W Fitzgerald Anne-Karin Kahlert Alejandro Sifrim Florian Wünnemann Yasset Perez-Riverol Hashim Abdul-Khaliq Mads Bak Anne S Bassett D Woodrow 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 Marshall Dianna M Milewicz Scott Lemaire Joseph S Coselli Michael E Mitchell Aoy Tomita-Mitchell Siddharth K Prakash Karl Stamm Alexandre F R Stewart Candice K Silversides 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 |
| author_sort |
Enrique Audain |
| title |
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| title_short |
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| title_full |
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| title_fullStr |
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| title_full_unstemmed |
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| title_sort |
integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/92067f3613e64d39b29f8fdaa8154ba8 |
| work_keys_str_mv |
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