ArticleProceedings of the National Academy of Sciences of the United States of America2025
Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes.
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Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Cardiac Organoids for Modeling Congenital Heart Disease: From Genetic Discovery to Therapeutic Screening.Current cardiology reports · 2026Review
- Functional genomics iniScience · 2026Article
- Whole-exome sequencing in individuals with obsessive-compulsive disorder and chronic tic disorders identifies 36 large-effect risk genes.Nature neuroscience · 2026Article
- Emerging genes implicated in human congenital heart disease: a 2023-2025 scoping review.Translational pediatrics · 2026Review
- MYH6 in Congenital Heart Defects: A Genotype-Phenotype Characterization in a French Cohort.Pediatric cardiology · 2026Article
- Sleep, Neural Circulatory Control, and Cardiovascular Disease: A Mechanistic Review.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Uniparental Disomy Reveals Hidden Genetic Causes of Congenital Heart Disease.Research square · 2026Article
- Genetic drivers of congenital cardiac fibrosis.Communications biology · 2026Review
- Mitochondrial dysfunction underlies cardiac contractility and growth defects in a zebrafish model ofbioRxiv : the preprint server for biology · 2026Article
- The inactive X chromosome as a female protector in autism and beyond.Nature genetics · 2026Review
- The oligogenic inheritance test GCOD detects risk genes and their interactions in congenital heart defects.Genome research · 2026Article
- A machine learning classifier to identify and prioritise genes associated with murine cardiac development.PLoS genetics · 2026Article
- Neural crest cell-derived DKK1 and NEDD4 modulate Wnt signalling in the second heart field to orchestrate outflow tract development.Nature communications · 2026Article
- Advances in interdisciplinary care for term and preterm neonates with congenital heart disease: a narrative review.European journal of pediatrics · 2026Review
- Gene4Denovo2: an updated platform for human de novo mutations discovery and interpretation.Nucleic acids research · 2026Article
- Multiomic Investigation of Shared Genetic Pathways in Paediatric Congenital Heart Disease and Neurodevelopmental Disorders.Human mutation · 2026Article
- A Novel STAG2 Frameshift Variant in Mullegama-Klein-Martinez Syndrome with Complex Conotruncal Heart Defect.Genes · 2025Article
- Maternal Genotype and Dietary Vitamin A Modify Aortic Arch Phenotypes in a Mouse Model of 22q11DS.International journal of molecular sciences · 2025Article
- Rare coding mutations identify 36 large-effect risk genes in obsessive-compulsive disorder and chronic tic disorders.medRxiv : the preprint server for health sciences · 2025Article
- Neuro-Genomic Mapping of Cardiac Neurons with Systemic Analysis Reveals Cognitive and Neurodevelopmental Impacts in Congenital Heart Disease.Life (Basel, Switzerland) · 2025Article
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Authors and funding
46 authors.
Michael C SierantDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.
Sheng Chih JinLaboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.
Kaya BilguvarDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.
Sarah U MortonDivision of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115.ORCID 0000-0002-7816-2646
Weilai DongDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0002-8376-1758
Wei JiangDepartment of Biostatistics, Yale School of Public Health, New Haven, CT 06510.
Ziyu LuLaboratory of Single-Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY 10065.
Boyang LiDepartment of Biostatistics, Yale School of Public Health, New Haven, CT 06510.
Francesc López-GiráldezYale Center for Genome Analysis, Yale University, New Haven, CT 06516.ORCID 0000-0001-7476-9822
Irina TikhonovaYale Center for Genome Analysis, Yale University, New Haven, CT 06516.
Xue ZengDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.
Qiongshi LuDepartment of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI 53706.ORCID 0000-0002-4514-0969
Jungmin ChoiDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0002-8614-0973
Junhui ZhangDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0003-0049-8032
Carol Nelson-WilliamsDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.
James R KnightYale Center for Genome Analysis, Yale University, New Haven, CT 06516.
Hongyu ZhaoDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0003-1195-9607
Junyue CaoLaboratory of Single-Cell Genomics and Population Dynamics, The Rockefeller University, New York, NY 10065.
Shrikant ManeYale Center for Genome Analysis, Yale University, New Haven, CT 06516.
Stanley C SedoreDepartment of Pediatrics, Section of Cardiology, Yale School of Medicine, New Haven, CT 06510.
Peter J GruberDepartment of Surgery, Yale University School of Medicine, New Haven, CT 06510.
Monkol LekDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.
Elizabeth GoldmuntzDivision of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
John DeanfieldInstitute of Cardiovascular Science, University College London, London WC1E 6BT, United Kingdom.
Alessandro GiardiniPediatric Cardiology, Great Ormond Street Hospital, London WC1N 3JH, United Kingdom.
Seema MitalDivision of Cardiology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G1X8, Canada.ORCID 0000-0002-7643-4484
Mark RussellDepartment of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109.
J William GaynorDivision of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Eileen KingDepartment of Pediatrics, University of Cincinnati, Cincinnati, OH 45229.
Michael WagnerDivision of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Deepak SrivastavaGladstone Institute of Cardiovascular Disease and University of California San Francisco, San Francisco, CA 94158.
Yufeng ShenDepartment of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032.
Daniel BernsteinDepartment of Pediatrics, Cardiology, Stanford University, Stanford, CA 94304.ORCID 0000-0001-7761-5853
George A PorterDepartment of Pediatrics, Section of Cardiology, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0003-0726-9988
Jane W NewburgerDepartment of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Jonathan G SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA 02115.ORCID 0000-0002-9082-3566
Amy E RobertsDepartment of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Mark YandellDepartment of Human Genetics, University of Utah and School of Medicine, Salt Lake City, UT 84112.
H Joseph YostDepartment of Human Genetics, University of Utah and School of Medicine, Salt Lake City, UT 84112.ORCID 0000-0003-2961-5669
Martin Tristani-FirouziDivision of Pediatric Cardiology, University of Utah, Salt Lake City, UT 84112.
Richard KimPediatric Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
Wendy K ChungDepartment of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
Bruce D GelbMindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Christine E SeidmanCardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115.ORCID 0000-0001-6380-1209
Martina BruecknerDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0003-0347-5389
Richard P LiftonLaboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.ORCID 0000-0002-5745-5984
Funding
Administrative Coordinating Center: Cardiovascular Development and Pediatric Cardiac Genomics ConsortiaU01HL131003 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI CNOTA, JAMES, OLLBERDING, NICHOLAS J · 2016 to 2024
$54.8MInstitutional Clinical and Translational Science AwardUL1TR000003 · NCATS · UNIVERSITY OF PENNSYLVANIA · PI FITZGERALD, GARRET A · 2012 to 2015
$38.9MCenter for Integrated Cellular Analysis - Valeria A. Sanchez EstradaRM1HG011014 · NHGRI · NEW YORK GENOME CENTER · PI LANDAU, DAN, SATIJA, RAHUL · 2020 to 2025
$22.1MYale Center for Mendelian DisordersU54HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2012 to 2015
$11.0MGENETICS AND GENOMICS OF HUMAN DISEASET32HD007149 · NICHD · YALE UNIVERSITY · PI James P Noonan · 1985 to 2026
$8.2MGenomic Effects on Right Ventricular Function, Clinical Features and Outcomes in CHDU01HL098147 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI NEWBURGER, JANE W., ROBERTS, AMY E · 2009 to 2024
$6.7MGenetic determinants of human heterotaxy and aortic arch malformationU01HL098162 · NHLBI · YALE UNIVERSITY · PI BRUECKNER, MARTINA, GRUBER, PETER J · 2009 to 2024
$5.9MThe Genetic Basis of Conotruncal DefectsU01HL098153 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI GOLDMUNTZ, ELIZABETH · 2009 to 2014
$4.3MIdentifying and applying genetic variation relevant to clinical outcomes for individuals with congenital heart diseaseU01HL153009 · NHLBI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CHUNG, WENDY K, GELB, BRUCE D · 2020 to 2024
$2.3MBridging the Gap between Genomics and Clinical Outcomes in CHDU01HL128711 · NHLBI · UNIVERSITY OF UTAH · PI TRISTANI-FIROUZI, MARTIN, YANDELL, MARK DOUGLAS · 2020 to 2024
$2.1MPediatric Heart Network - The Hospital for Sick Children, TorontoUG1HL135680 · NHLBI · HOSPITAL FOR SICK CHLDRN (TORONTO) · PI MCCRINDLE, BRIAN W, MITAL, SEEMA · 2017 to 2023
$1.7MIntegration of RNA and Genome Sequences to Identify Genetic Risk in Hypoplastic Left Heart SyndromeK08HL157653 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI Sarah Uhler Morton · 2022 to 2026
$840kAmerican Heart Association (AHA) 19PRE3438084Children's Discovery Institute (CDI) CDI-FR-2021-926HHMI (HHMI) HHMIHHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) NIH R03HD100883-A1HHS | NIH | National Center for Advancing Translational Sciences (NCATS) UL1TR000003HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 1UG1HL135680-01HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) HL157653HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) R00HL143036-02HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) UO1 HL098147HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) UO1 HL098162HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) UO1 HL128711HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) UO1 HL131003HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) UO1 HL153009HHS | NIH | National Human Genome Research Institute (NHGRI) 5U54HG006504HHS | NIH | National Human Genome Research Institute (NHGRI) RM1HG011014NCATS NIH HHS UL1 TR000003NHGRI NIH HHS RM1 HG011014NHGRI NIH HHS U54 HG006504NHLBI NIH HHS K08 HL157653NHLBI NIH HHS R00 HL143036NHLBI NIH HHS U01 HL098147NHLBI NIH HHS U01 HL098153NHLBI NIH HHS U01 HL098162NHLBI NIH HHS U01 HL128711NHLBI NIH HHS U01 HL131003NHLBI NIH HHS U01 HL153009NHLBI NIH HHS UG1 HL135680NICHD NIH HHS R03 HD100883NICHD NIH HHS T32 HD007149
Abstract
Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent-offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in
Indexed as
Genes, DominantHeart Defects, CongenitalFemaleGenetic Predisposition to DiseaseGenomicsHumansInfantMaleMutationMutation, MissenseMyosin Heavy ChainsReceptor, Notch1Myosin Heavy ChainsNOTCH1 protein, humanReceptor, Notch1congenital heart diseaseexome sequencinggenomicshuman geneticsmolecular inversion probes
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