Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Alejandro Sifrim; Marc-Phillip Hitz; Anna Wilsdon; Jeroen Breckpot; Saeed H Al Turki; Bernard Thienpont; Jeremy McRae; Tomas W Fitzgerald; Tarjinder Singh; Ganesh Jawahar Swaminathan; Elena Prigmore; Diana Rajan; Hashim Abdul-Khaliq; Siddharth Banka; Ulrike M M Bauer; Jamie Bentham; Felix Berger; Shoumo Bhattacharya; Frances Bu'Lock; Natalie Canham; Irina-Gabriela Colgiu; Catherine Cosgrove; Helen Cox; Ingo Daehnert; Allan Daly; John Danesh; Alan Fryer; Marc Gewillig; Emma Hobson; Kirstin Hoff; Tessa Homfray; Anne-Karin Kahlert; Ami Ketley; Hans-Heiner Kramer; Katherine Lachlan; Anne Katrin Lampe; Jacoba J Louw; Ashok Kumar Manickara; Dorin Manase; Karen P McCarthy; Kay Metcalfe; Carmel Moore; Ruth Newbury-Ecob; Seham Osman Omer; Willem H Ouwehand; Soo-Mi Park; Michael J Parker; Thomas Pickardt; Martin O Pollard; Bernard Keavney; INTERVAL Study

doi:10.1038/ng.3627

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Alejandro Sifrim
, Marc-Phillip Hitz
, Anna Wilsdon
, Jeroen Breckpot
, Saeed H Al Turki
, Bernard Thienpont
, Jeremy McRae
, Tomas W Fitzgerald
, Tarjinder Singh
, Ganesh Jawahar Swaminathan
, Elena Prigmore
, Diana Rajan
, Hashim Abdul-Khaliq
, Siddharth Banka
, Ulrike M M Bauer
, Jamie Bentham
, Felix Berger
, Shoumo Bhattacharya
, Frances Bu'Lock
, Natalie Canham

Irina-Gabriela Colgiu, Catherine Cosgrove, Helen Cox, Ingo Daehnert, Allan Daly, John Danesh, Alan Fryer, Marc Gewillig, Emma Hobson, Kirstin Hoff, Tessa Homfray, Anne-Karin Kahlert, Ami Ketley, Hans-Heiner Kramer, Katherine Lachlan, Anne Katrin Lampe, Jacoba J Louw, Ashok Kumar Manickara, Dorin Manase, Karen P McCarthy, Kay Metcalfe, Carmel Moore, Ruth Newbury-Ecob, Seham Osman Omer, Willem H Ouwehand, Soo-Mi Park, Michael J Parker, Thomas Pickardt, Martin O Pollard, Bernard Keavney, INTERVAL Study

VIB vwz
Yorkshire Heart Centre
Bristol NHS Foundation Trust
Sheffield Children's NHS Foundation Trust
Manchester Academic Health Science Centre (MAHSC)
Central Manchester University Hospitals NHS Foundation Trust
Royal Brompton Hospital
Imperial College London
Western General Hospital
University Hospital Southampton NHS Foundation Trust
Princess Anne Hospital
Universitatsklinikum Schleswig Holstein
University of Nottingham
Saarland University
London North West Healthcare NHS Trust
Liverpool Women's NHS Foundation Trust
St George's Healthcare NHS Trust
Leeds Teaching Hospitals NHS Trust
Wellcome Trust Sanger Institute
University of Nottingham
Queen's Medical Centre
Katholieke Universiteit Leuven
Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK
German Center for Cardiovascular Research (DZHK)
Oxford University
East Midlands Congenital Heart Centre
Birmingham Women's NHS Foundation Trust
The Hospital for Sick Children
University of Cambridge
King Abdulaziz Medical City
King Abdulaziz Cardiac Center
Cambridge University Hospitals NHS Foundation Trust

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Abstract

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 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.

Original language	English
Pages (from-to)	1060-5
Number of pages	6
Journal	Nature Genetics
Volume	48
Issue number	9
Early online date	1 Aug 2016
DOIs	https://doi.org/10.1038/ng.3627
Publication status	Published - Sept 2016

Keywords

Journal Article

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10.1038/ng.3627

51512010.44827_2_merged_1466791820Accepted author manuscript, 4.55 MB

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Sifrim, A., Hitz, M.-P., Wilsdon, A., Breckpot, J., Turki, S. H. A., Thienpont, B., McRae, J., Fitzgerald, T. W., Singh, T., Swaminathan, G. J., Prigmore, E., Rajan, D., Abdul-Khaliq, H., Banka, S., Bauer, U. M. M., Bentham, J., Berger, F., Bhattacharya, S., Bu'Lock, F., ... INTERVAL Study (2016). Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics, 48(9), 1060-5. https://doi.org/10.1038/ng.3627

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title = "Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing",

abstract = "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 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.",

keywords = "Journal Article",

author = "Alejandro Sifrim and Marc-Phillip Hitz and Anna Wilsdon and Jeroen Breckpot and Turki, \{Saeed H Al\} and Bernard Thienpont and Jeremy McRae and Fitzgerald, \{Tomas W\} and Tarjinder Singh and Swaminathan, \{Ganesh Jawahar\} and Elena Prigmore and Diana Rajan and Hashim Abdul-Khaliq and Siddharth Banka and Bauer, \{Ulrike M M\} and Jamie Bentham and Felix Berger and Shoumo Bhattacharya and Frances Bu'Lock and Natalie Canham and Irina-Gabriela Colgiu and Catherine Cosgrove and Helen Cox and Ingo Daehnert and Allan Daly and John Danesh and Alan Fryer and Marc Gewillig and Emma Hobson and Kirstin Hoff and Tessa Homfray and Anne-Karin Kahlert and Ami Ketley and Hans-Heiner Kramer and Katherine Lachlan and Lampe, \{Anne Katrin\} and Louw, \{Jacoba J\} and Manickara, \{Ashok Kumar\} and Dorin Manase and McCarthy, \{Karen P\} and Kay Metcalfe and Carmel Moore and Ruth Newbury-Ecob and Omer, \{Seham Osman\} and Ouwehand, \{Willem H\} and Soo-Mi Park and Parker, \{Michael J\} and Thomas Pickardt and Pollard, \{Martin O\} and Bernard Keavney and \{INTERVAL Study\}",

year = "2016",

month = sep,

doi = "10.1038/ng.3627",

language = "English",

volume = "48",

pages = "1060--5",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Sifrim, A, Hitz, M-P, Wilsdon, A, Breckpot, J, Turki, SHA, Thienpont, B, McRae, J, Fitzgerald, TW, Singh, T, Swaminathan, GJ, Prigmore, E, Rajan, D, Abdul-Khaliq, H, Banka, S, Bauer, UMM, Bentham, J, Berger, F, Bhattacharya, S, Bu'Lock, F, Canham, N, Colgiu, I-G, Cosgrove, C, Cox, H, Daehnert, I, Daly, A, Danesh, J, Fryer, A, Gewillig, M, Hobson, E, Hoff, K, Homfray, T, Kahlert, A-K, Ketley, A, Kramer, H-H, Lachlan, K, Lampe, AK, Louw, JJ, Manickara, AK, Manase, D, McCarthy, KP, Metcalfe, K, Moore, C, Newbury-Ecob, R, Omer, SO, Ouwehand, WH, Park, S-M, Parker, MJ, Pickardt, T, Pollard, MO, Keavney, B & INTERVAL Study 2016, 'Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing', Nature Genetics, vol. 48, no. 9, pp. 1060-5. https://doi.org/10.1038/ng.3627

TY - JOUR

T1 - Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

AU - Sifrim, Alejandro

AU - Hitz, Marc-Phillip

AU - Wilsdon, Anna

AU - Breckpot, Jeroen

AU - Turki, Saeed H Al

AU - Thienpont, Bernard

AU - McRae, Jeremy

AU - Fitzgerald, Tomas W

AU - Singh, Tarjinder

AU - Swaminathan, Ganesh Jawahar

AU - Prigmore, Elena

AU - Rajan, Diana

AU - Abdul-Khaliq, Hashim

AU - Banka, Siddharth

AU - Bauer, Ulrike M M

AU - Bentham, Jamie

AU - Berger, Felix

AU - Bhattacharya, Shoumo

AU - Bu'Lock, Frances

AU - Canham, Natalie

AU - Colgiu, Irina-Gabriela

AU - Cosgrove, Catherine

AU - Cox, Helen

AU - Daehnert, Ingo

AU - Daly, Allan

AU - Danesh, John

AU - Fryer, Alan

AU - Gewillig, Marc

AU - Hobson, Emma

AU - Hoff, Kirstin

AU - Homfray, Tessa

AU - Kahlert, Anne-Karin

AU - Ketley, Ami

AU - Kramer, Hans-Heiner

AU - Lachlan, Katherine

AU - Lampe, Anne Katrin

AU - Louw, Jacoba J

AU - Manickara, Ashok Kumar

AU - Manase, Dorin

AU - McCarthy, Karen P

AU - Metcalfe, Kay

AU - Moore, Carmel

AU - Newbury-Ecob, Ruth

AU - Omer, Seham Osman

AU - Ouwehand, Willem H

AU - Park, Soo-Mi

AU - Parker, Michael J

AU - Pickardt, Thomas

AU - Pollard, Martin O

AU - Keavney, Bernard

AU - INTERVAL Study

PY - 2016/9

Y1 - 2016/9

N2 - 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 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.

AB - 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 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.

KW - Journal Article

UR - https://www.scopus.com/pages/publications/84980370998

U2 - 10.1038/ng.3627

DO - 10.1038/ng.3627

M3 - Article

C2 - 27479907

SN - 1061-4036

VL - 48

SP - 1060

EP - 1065

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

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