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%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4,5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6,7. 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 findings8. 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.
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We thank the patients and their families for their participation and patience. The authors thank J. Lord for proofreading this manuscript and the Exome Aggregation Consortium for making their data available. The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The research team acknowledges the support of the National Institutes for Health Research through the Comprehensive Clinical Research Network. The authors wish to thank the Sanger Human Genome Informatics team, the DNA pipelines team and the Core Sequencing team for their support in generating and processing the data. We would like to thank the Pediatric Cardiac Genomics Consortium (PCGC) and dbGAP for making the data publicly available. This study was supported by the German Center for Cardiovascular Research (DZHK) partner sites Berlin, Kiel and Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England, which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre. The academic coordinating center for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and NIHR Research Cambridge Biomedical Research Centre. J.D.B., K.S. and A.K. are funded by British Heart Foundation Programme Grant RG/13/10/30376. A.W. is funded by a British Heart Foundation Clinical Fellowship FS/14/51/30879. D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. S.H.A.T., S.O.O. and R.M.A.-S. were supported by funding from King Abdullah International Medical Research Center (grant number RC12/037). J.B. was supported by the Klinisch Onderzoeksfonds UZ; B.T. was supported by the CHAMELEO Marie Curie Career Integration Grant; J.J.L. and M.G. Eddy Merckx Research grant. K.D. was funded by the GOA/2012/015 grant. A.K.M., D.M. and S.M. were supported by the Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research.
Integrated supplementary information
Inherited rare PTVs in Tier 1 monoallelic CHD genes
Results of de novo enrichment analysis in the S-CHD cohort
Results of de novo enrichment analysis in the "unresolved" S-CHD cohort
Clinical description of probands carrying de novo mutations in CDK13
Clinical description of probands carrying de novo mutations in CHD4
Clinical description of probands carrying de novo mutations in PRKD1
Manual review of top-ranking genes from the (TADA) integrated de novo and inherited variant analysis
Results of InnateDB Gene Ontology overrepresentation analysis
Results of InnateDB Pathway overrepresentation analysis
Overview of main analyses and their primary conclusions
Manually curated set of known CHD-genes by tier and inheritance mode
List of de novo variants in S-CHD cases called by DeNovoGear after filtering criteria were applied
List of de novo variants in NS-CHD cases called by DeNovoGear after filtering criteria were applied
List of de novo variants in S-CHD-DX cases (syndromic cases with no de novo variants in known developmental disorder genes) called by DeNovoGear after filtering criteria were applied
1241 rare CNV calls made by CoNVex and passing automatic and manual quality control
31 CNV calls overlapping known CHD-associated genes or top-ranking genes (FDR<10%) from the integrated de novo and inherited variant analysis
Results of the integrated (TADA) de novo and inherited rare variant analysis
About this article
De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes
Nature Communications (2019)