Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1%. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-trunca...
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| Format: | Article |
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Nature Publishing Group
2016
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| Online Access: | https://eprints.nottingham.ac.uk/38584/ |
| _version_ | 1848795645848059904 |
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| author | Sifrim, Alejandro Hitz, Marc-Phillip Wilsdon, Anna Breckpot, Jeroen Turki, Saeed H Al Thienpont, Bernard McRae, Jeremy Fitzgerald, Tomas W Singh, Tarjinder Swaminathan, Ganesh Jawahar Prigmore, Elena Rajan, Diana Abdul-Khaliq, Hashim Banka, Siddharth Bauer, Ulrike M.M. Bentham, Jamie Berger, Felix Bhattacharya, Shoumo Bu'Lock, Frances A. Canham, Natalie Colgiu, Irina-Gabriela Cosgrove, Catherine Cox, Helen Daehnert, Ingo Daly, Allan Danesh, John Fryer, Alan Gewillig, Marc Hobson, Emma Hoff, Kirstin Homfray, Tessa Kahlert, Anne-Karin Ketley, Ami Kramer, Hans-Heiner Lachlan, Katherine Lampe, Anne Katrin Louw, Jacoba J. Manickara, Ashok Kumar Manase, Dorin McCarthy, Karen P. Metcalfe, Kay Moore, Carmel Newbury-Ecob, Ruth Omer, Seham Osman Ouwehand, Willem H. Park, Soo-Mi Parker, Michael J. Pickardt, Thomas Pollard, Martin O. Robert, Leema Roberts, David J. Sambrook, Jennifer Setchfield, Kerry Stiller, Brigitte Thornborough, Christopher Toka, Okan Watkins, Hugh Williams, Denise Wright, Michael Mital, Seema Daubeney, Piers E.F. Keavney, Bernard Goodship, Judith Abu-Sulaiman, Riyadh Mahdi Klaassen, Sabine Wright, Caroline F. Firth, Helen V. Barrett, Jeffrey C. Devriendt, Koenraad FitzPatrick, David R. Brook, J. David Hurles, Matthew E. |
| author_facet | Sifrim, Alejandro Hitz, Marc-Phillip Wilsdon, Anna Breckpot, Jeroen Turki, Saeed H Al Thienpont, Bernard McRae, Jeremy Fitzgerald, Tomas W Singh, Tarjinder Swaminathan, Ganesh Jawahar Prigmore, Elena Rajan, Diana Abdul-Khaliq, Hashim Banka, Siddharth Bauer, Ulrike M.M. Bentham, Jamie Berger, Felix Bhattacharya, Shoumo Bu'Lock, Frances A. Canham, Natalie Colgiu, Irina-Gabriela Cosgrove, Catherine Cox, Helen Daehnert, Ingo Daly, Allan Danesh, John Fryer, Alan Gewillig, Marc Hobson, Emma Hoff, Kirstin Homfray, Tessa Kahlert, Anne-Karin Ketley, Ami Kramer, Hans-Heiner Lachlan, Katherine Lampe, Anne Katrin Louw, Jacoba J. Manickara, Ashok Kumar Manase, Dorin McCarthy, Karen P. Metcalfe, Kay Moore, Carmel Newbury-Ecob, Ruth Omer, Seham Osman Ouwehand, Willem H. Park, Soo-Mi Parker, Michael J. Pickardt, Thomas Pollard, Martin O. Robert, Leema Roberts, David J. Sambrook, Jennifer Setchfield, Kerry Stiller, Brigitte Thornborough, Christopher Toka, Okan Watkins, Hugh Williams, Denise Wright, Michael Mital, Seema Daubeney, Piers E.F. Keavney, Bernard Goodship, Judith Abu-Sulaiman, Riyadh Mahdi Klaassen, Sabine Wright, Caroline F. Firth, Helen V. Barrett, Jeffrey C. Devriendt, Koenraad FitzPatrick, David R. Brook, J. David Hurles, Matthew E. |
| author_sort | Sifrim, Alejandro |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1%. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD. |
| first_indexed | 2025-11-14T19:35:23Z |
| format | Article |
| id | nottingham-38584 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:35:23Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-385842020-05-04T17:58:41Z https://eprints.nottingham.ac.uk/38584/ Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing Sifrim, Alejandro Hitz, Marc-Phillip Wilsdon, Anna Breckpot, Jeroen Turki, Saeed H Al Thienpont, Bernard McRae, Jeremy Fitzgerald, Tomas W Singh, Tarjinder Swaminathan, Ganesh Jawahar Prigmore, Elena Rajan, Diana Abdul-Khaliq, Hashim Banka, Siddharth Bauer, Ulrike M.M. Bentham, Jamie Berger, Felix Bhattacharya, Shoumo Bu'Lock, Frances A. Canham, Natalie Colgiu, Irina-Gabriela Cosgrove, Catherine Cox, Helen Daehnert, Ingo Daly, Allan Danesh, John Fryer, Alan Gewillig, Marc Hobson, Emma Hoff, Kirstin Homfray, Tessa Kahlert, Anne-Karin Ketley, Ami Kramer, Hans-Heiner Lachlan, Katherine Lampe, Anne Katrin Louw, Jacoba J. Manickara, Ashok Kumar Manase, Dorin McCarthy, Karen P. Metcalfe, Kay Moore, Carmel Newbury-Ecob, Ruth Omer, Seham Osman Ouwehand, Willem H. Park, Soo-Mi Parker, Michael J. Pickardt, Thomas Pollard, Martin O. Robert, Leema Roberts, David J. Sambrook, Jennifer Setchfield, Kerry Stiller, Brigitte Thornborough, Christopher Toka, Okan Watkins, Hugh Williams, Denise Wright, Michael Mital, Seema Daubeney, Piers E.F. Keavney, Bernard Goodship, Judith Abu-Sulaiman, Riyadh Mahdi Klaassen, Sabine Wright, Caroline F. Firth, Helen V. Barrett, Jeffrey C. Devriendt, Koenraad FitzPatrick, David R. Brook, J. David Hurles, Matthew E. Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1%. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD. Nature Publishing Group 2016-08-01 Article PeerReviewed Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Turki, Saeed H Al, Thienpont, Bernard, McRae, Jeremy, Fitzgerald, Tomas W, Singh, Tarjinder, Swaminathan, Ganesh Jawahar, Prigmore, Elena, Rajan, Diana, Abdul-Khaliq, Hashim, Banka, Siddharth, Bauer, Ulrike M.M., Bentham, Jamie, Berger, Felix, Bhattacharya, Shoumo, Bu'Lock, Frances A., Canham, Natalie, Colgiu, Irina-Gabriela, Cosgrove, Catherine, Cox, Helen, Daehnert, Ingo, Daly, Allan, Danesh, John, Fryer, Alan, Gewillig, Marc, Hobson, Emma, Hoff, Kirstin, Homfray, Tessa, Kahlert, Anne-Karin, Ketley, Ami, Kramer, Hans-Heiner, Lachlan, Katherine, Lampe, Anne Katrin, Louw, Jacoba J., Manickara, Ashok Kumar, Manase, Dorin, McCarthy, Karen P., Metcalfe, Kay, Moore, Carmel, Newbury-Ecob, Ruth, Omer, Seham Osman, Ouwehand, Willem H., Park, Soo-Mi, Parker, Michael J., Pickardt, Thomas, Pollard, Martin O., Robert, Leema, Roberts, David J., Sambrook, Jennifer, Setchfield, Kerry, Stiller, Brigitte, Thornborough, Christopher, Toka, Okan, Watkins, Hugh, Williams, Denise, Wright, Michael, Mital, Seema, Daubeney, Piers E.F., Keavney, Bernard, Goodship, Judith, Abu-Sulaiman, Riyadh Mahdi, Klaassen, Sabine, Wright, Caroline F., Firth, Helen V., Barrett, Jeffrey C., Devriendt, Koenraad, FitzPatrick, David R., Brook, J. David and Hurles, Matthew E. (2016) Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics, 48 (9). pp. 1060-1065. ISSN 1546-1718 Clinical Genetics Congenital Heart Defects Genetics Research http://www.nature.com/ng/journal/v48/n9/full/ng.3627.html doi:10.1038/ng.3627 doi:10.1038/ng.3627 |
| spellingShingle | Clinical Genetics Congenital Heart Defects Genetics Research Sifrim, Alejandro Hitz, Marc-Phillip Wilsdon, Anna Breckpot, Jeroen Turki, Saeed H Al Thienpont, Bernard McRae, Jeremy Fitzgerald, Tomas W Singh, Tarjinder Swaminathan, Ganesh Jawahar Prigmore, Elena Rajan, Diana Abdul-Khaliq, Hashim Banka, Siddharth Bauer, Ulrike M.M. Bentham, Jamie Berger, Felix Bhattacharya, Shoumo Bu'Lock, Frances A. Canham, Natalie Colgiu, Irina-Gabriela Cosgrove, Catherine Cox, Helen Daehnert, Ingo Daly, Allan Danesh, John Fryer, Alan Gewillig, Marc Hobson, Emma Hoff, Kirstin Homfray, Tessa Kahlert, Anne-Karin Ketley, Ami Kramer, Hans-Heiner Lachlan, Katherine Lampe, Anne Katrin Louw, Jacoba J. Manickara, Ashok Kumar Manase, Dorin McCarthy, Karen P. Metcalfe, Kay Moore, Carmel Newbury-Ecob, Ruth Omer, Seham Osman Ouwehand, Willem H. Park, Soo-Mi Parker, Michael J. Pickardt, Thomas Pollard, Martin O. Robert, Leema Roberts, David J. Sambrook, Jennifer Setchfield, Kerry Stiller, Brigitte Thornborough, Christopher Toka, Okan Watkins, Hugh Williams, Denise Wright, Michael Mital, Seema Daubeney, Piers E.F. Keavney, Bernard Goodship, Judith Abu-Sulaiman, Riyadh Mahdi Klaassen, Sabine Wright, Caroline F. Firth, Helen V. Barrett, Jeffrey C. Devriendt, Koenraad FitzPatrick, David R. Brook, J. David Hurles, Matthew E. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| title | Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| title_full | Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| title_fullStr | Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| title_full_unstemmed | Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| title_short | Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| title_sort | distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing |
| topic | Clinical Genetics Congenital Heart Defects Genetics Research |
| url | https://eprints.nottingham.ac.uk/38584/ https://eprints.nottingham.ac.uk/38584/ https://eprints.nottingham.ac.uk/38584/ |