Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
<p>Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). 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. D...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2016
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| _version_ | 1797067235862249472 |
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| author | Sifrim, A Hitz, M Wilsdon, A Breckpot, J Al Turki, S Thienpont, B McRae, J Fitzgerald, T Singh, T Swaminathan, G Prigmore, E Rajan, D Abdul-Khaliq, H Banka, S Bauer, U Bentham, J Berger, F Bhattacharya, S Bu'Lock, F Canham, N Colgiu, I Cosgrove, C Cox, H Daehnert, I Daly, A Danesh, J Fryer, A Gewillig, M Hobson, E Hoff, K Homfray, T Kahlert, A Ketley, A Kramer, H Lachlan, K Lampe, A Louw, J Manickara, A Manase, D McCarthy, K Metcalfe, K Moore, C Newbury-Ecob, R Omer, S Ouwehand, W Park, S Parker, M Pickardt, T Pollard, M Robert, L Roberts, D Sambrook, J Setchfield, K Stiller, B Thornborough, C Toka, O Watkins, H Williams, D Wright, M Mital, S Daubeney, P Keavney, B Goodship, J Abu-Sulaiman, R Klaassen, S Wright, C Firth, H Barrett, J Devriendt, K FitzPatrick, D Brook, J Hurles, M |
| author_facet | Sifrim, A Hitz, M Wilsdon, A Breckpot, J Al Turki, S Thienpont, B McRae, J Fitzgerald, T Singh, T Swaminathan, G Prigmore, E Rajan, D Abdul-Khaliq, H Banka, S Bauer, U Bentham, J Berger, F Bhattacharya, S Bu'Lock, F Canham, N Colgiu, I Cosgrove, C Cox, H Daehnert, I Daly, A Danesh, J Fryer, A Gewillig, M Hobson, E Hoff, K Homfray, T Kahlert, A Ketley, A Kramer, H Lachlan, K Lampe, A Louw, J Manickara, A Manase, D McCarthy, K Metcalfe, K Moore, C Newbury-Ecob, R Omer, S Ouwehand, W Park, S Parker, M Pickardt, T Pollard, M Robert, L Roberts, D Sambrook, J Setchfield, K Stiller, B Thornborough, C Toka, O Watkins, H Williams, D Wright, M Mital, S Daubeney, P Keavney, B Goodship, J Abu-Sulaiman, R Klaassen, S Wright, C Firth, H Barrett, J Devriendt, K FitzPatrick, D Brook, J Hurles, M |
| author_sort | Sifrim, A |
| collection | OXFORD |
| description | <p>Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). 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 proteintruncating 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.</p> |
| first_indexed | 2024-03-06T21:53:29Z |
| format | Journal article |
| id | oxford-uuid:4c1e2dbc-4051-43f5-8c93-7389ef90e024 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:53:29Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:4c1e2dbc-4051-43f5-8c93-7389ef90e0242022-03-26T15:47:45ZDistinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4c1e2dbc-4051-43f5-8c93-7389ef90e024EnglishSymplectic Elements at OxfordNature Publishing Group2016Sifrim, AHitz, MWilsdon, ABreckpot, JAl Turki, SThienpont, BMcRae, JFitzgerald, TSingh, TSwaminathan, GPrigmore, ERajan, DAbdul-Khaliq, HBanka, SBauer, UBentham, JBerger, FBhattacharya, SBu'Lock, FCanham, NColgiu, ICosgrove, CCox, HDaehnert, IDaly, ADanesh, JFryer, AGewillig, MHobson, EHoff, KHomfray, TKahlert, AKetley, AKramer, HLachlan, KLampe, ALouw, JManickara, AManase, DMcCarthy, KMetcalfe, KMoore, CNewbury-Ecob, ROmer, SOuwehand, WPark, SParker, MPickardt, TPollard, MRobert, LRoberts, DSambrook, JSetchfield, KStiller, BThornborough, CToka, OWatkins, HWilliams, DWright, MMital, SDaubeney, PKeavney, BGoodship, JAbu-Sulaiman, RKlaassen, SWright, CFirth, HBarrett, JDevriendt, KFitzPatrick, DBrook, JHurles, M<p>Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). 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 proteintruncating 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.</p> |
| spellingShingle | Sifrim, A Hitz, M Wilsdon, A Breckpot, J Al Turki, S Thienpont, B McRae, J Fitzgerald, T Singh, T Swaminathan, G Prigmore, E Rajan, D Abdul-Khaliq, H Banka, S Bauer, U Bentham, J Berger, F Bhattacharya, S Bu'Lock, F Canham, N Colgiu, I Cosgrove, C Cox, H Daehnert, I Daly, A Danesh, J Fryer, A Gewillig, M Hobson, E Hoff, K Homfray, T Kahlert, A Ketley, A Kramer, H Lachlan, K Lampe, A Louw, J Manickara, A Manase, D McCarthy, K Metcalfe, K Moore, C Newbury-Ecob, R Omer, S Ouwehand, W Park, S Parker, M Pickardt, T Pollard, M Robert, L Roberts, D Sambrook, J Setchfield, K Stiller, B Thornborough, C Toka, O Watkins, H Williams, D Wright, M Mital, S Daubeney, P Keavney, B Goodship, J Abu-Sulaiman, R Klaassen, S Wright, C Firth, H Barrett, J Devriendt, K FitzPatrick, D Brook, J Hurles, M 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 |
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