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% (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.

Citing Articles

Two distinct phenotypes in Snijders Blok-Campeau syndrome and characterization of the behavioral phenotype in a zebrafish model.

Enomoto Y, Shiromizu T, Yasojima S, Koiwa J, Kuroda Y, Ito H Eur J Hum Genet. 2025; .

PMID: 39988727 DOI: 10.1038/s41431-025-01815-y.

Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft.

Jeong R, Bulyk M medRxiv. 2025; .

PMID: 39974057 PMC: 11838631. DOI: 10.1101/2025.01.30.25321274.

Genetic impact of copy number variations on congenital heart defects: Current insights and future directions.

Krishnamurthy N, Krishna D, Sanjana , Rathinasamy J, Kumar A, Francis A Glob Med Genet. 2025; 12(1):100008.

PMID: 39925442 PMC: 11800308. DOI: 10.1016/j.gmg.2024.100008.

Chromosomal analysis and short-term outcome of prenatally diagnosed congenital heart disease.

Verbeke M, Hannes L, Devriendt K, Van den Bogaert K, Cools B, De Catte L Sci Rep. 2025; 15(1):3923.

PMID: 39890866 PMC: 11785992. DOI: 10.1038/s41598-025-88570-8.

Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome.

Karimi K, Lichtenstein Y, Reilly J, McConkey H, Relator R, Levy M Am J Hum Genet. 2025; 112(2):414-427.

PMID: 39824190 PMC: 11866970. DOI: 10.1016/j.ajhg.2024.12.020.

References

Shaheen R, Al Hashem A, Alghamdi M, Seidahmad M, Wakil S, Dagriri K . Positional mapping of PRKD1, NRP1 and PRDM1 as novel candidate disease genes in truncus arteriosus. J Med Genet. 2015; 52(5):322-9. DOI: 10.1136/jmedgenet-2015-102992. View

Breuer K, Foroushani A, Laird M, Chen C, Sribnaia A, Lo R . InnateDB: systems biology of innate immunity and beyond--recent updates and continuing curation. Nucleic Acids Res. 2012; 41(Database issue):D1228-33. PMC: 3531080. DOI: 10.1093/nar/gks1147. View

Li Y, Klena N, Gabriel G, Liu X, Kim A, Lemke K . Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature. 2015; 521(7553):520-4. PMC: 4617540. DOI: 10.1038/nature14269. View

Oyen N, Poulsen G, Boyd H, Wohlfahrt J, Jensen P, Melbye M . Recurrence of congenital heart defects in families. Circulation. 2009; 120(4):295-301. DOI: 10.1161/CIRCULATIONAHA.109.857987. View

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

Ramu A, Noordam M, Schwartz R, Wuster A, Hurles M, Cartwright R . DeNovoGear: de novo indel and point mutation discovery and phasing. Nat Methods. 2013; 10(10):985-7. PMC: 4003501. DOI: 10.1038/nmeth.2611. View

He X, Sanders S, Liu L, De Rubeis S, Lim E, Sutcliffe J . Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Genet. 2013; 9(8):e1003671. PMC: 3744441. DOI: 10.1371/journal.pgen.1003671. View

Bauer R, Laney A, Smith R, Gerfen J, Morrissette J, Woyciechowski S . Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis. Hum Mutat. 2010; 31(5):594-601. PMC: 2914103. DOI: 10.1002/humu.21231. View

Kiezun A, Garimella K, Do R, Stitziel N, Neale B, McLaren P . Exome sequencing and the genetic basis of complex traits. Nat Genet. 2012; 44(6):623-30. PMC: 3727622. DOI: 10.1038/ng.2303. View

10.

Hoffman J, Kaplan S . The incidence of congenital heart disease. J Am Coll Cardiol. 2002; 39(12):1890-900. DOI: 10.1016/s0735-1097(02)01886-7. View

11.

Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton J . De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013; 498(7453):220-3. PMC: 3706629. DOI: 10.1038/nature12141. View

12.

. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2014; 519(7542):223-8. PMC: 5955210. DOI: 10.1038/nature14135. View

13.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

14.

Giroud J, Jacobs J, Spicer D, Backer C, Martin G, Franklin R . Report from the international society for nomenclature of paediatric and congenital heart disease: creation of a visual encyclopedia illustrating the terms and definitions of the international pediatric and congenital cardiac code. World J Pediatr Congenit Heart Surg. 2013; 1(3):300-13. DOI: 10.1177/2150135110379622. View

15.

Robinson P, Kohler S, Bauer S, Seelow D, Horn D, Mundlos S . The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet. 2008; 83(5):610-5. PMC: 2668030. DOI: 10.1016/j.ajhg.2008.09.017. View

16.

Pierpont M, Basson C, Benson Jr D, Gelb B, Giglia T, Goldmuntz E . Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of.... Circulation. 2007; 115(23):3015-38. DOI: 10.1161/CIRCULATIONAHA.106.183056. View

17.

Fielitz J, Kim M, Shelton J, Qi X, Hill J, Richardson J . Requirement of protein kinase D1 for pathological cardiac remodeling. Proc Natl Acad Sci U S A. 2008; 105(8):3059-63. PMC: 2268584. DOI: 10.1073/pnas.0712265105. View

18.

Samocha K, Robinson E, Sanders S, Stevens C, Sabo A, McGrath L . A framework for the interpretation of de novo mutation in human disease. Nat Genet. 2014; 46(9):944-50. PMC: 4222185. DOI: 10.1038/ng.3050. View

19.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

20.

Blazek D, Kohoutek J, Bartholomeeusen K, Johansen E, Hulinkova P, Luo Z . The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev. 2011; 25(20):2158-72. PMC: 3205586. DOI: 10.1101/gad.16962311. View