ArticleProceedings of the National Academy of Sciences of the United States of America2025
Recessive genetic contribution to congenital heart disease in 5,424 probands.
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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 16 papers, 2 of them syntheses that pooled it.
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16citing papers in PubMed, 2 pooled it
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Who cites it
16 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Genetics in Heterotaxy: A Case Series and Literature Review on DNAH9, PKD1L1, MMP21, and GDF1.Clinical genetics · 2026Pooled it
- Yield of Whole Genome Sequencing for Pathogenic Single Nucleotide Variants in Congenital Heart Disease: A Systematic Review and Meta-Analysis.Prenatal diagnosis · 2026Pooled it
- Article
- Decoding Long Noncoding RNAs in Cardiac Development and Congenital Heart Disease: Recent Advances and Clinical Perspectives.Circulation. Genomic and precision medicine · 2026Review
- Functional genomics iniScience · 2026Article
- Emerging genes implicated in human congenital heart disease: a 2023-2025 scoping review.Translational pediatrics · 2026Review
- Uniparental Disomy Reveals Hidden Genetic Causes of Congenital Heart Disease.Research square · 2026Article
- Article
- Patient-informed CRISPR screen identifies FLNB as a congenital heart disease and ciliopathy gene.HGG advances · 2026Article
- A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects.Nature cardiovascular research · 2026Article
- Novel compound heterozygous variants in theFrontiers in cardiovascular medicine · 2026Article
- Genomic spectrum of congenital heart disease combined with kidney and urinary tract anomalies uncovered by exome sequencing and array-CGH.Frontiers in cell and developmental biology · 2026Article
- Maternal Genotype and Dietary Vitamin A Modify Aortic Arch Phenotypes in a Mouse Model of 22q11DS.International journal of molecular sciences · 2025Article
- Patient-informed CRISPR Screen Identifies FLNB as a Novel Congenital Heart Disease and Ciliopathy Gene.bioRxiv : the preprint server for biology · 2025Article
- Integrative Functional Genomics Identifies ARHGAP10 in the 4q31.2 Locus as a Novel Congenital Heart Disease and Ciliopathy Gene.bioRxiv : the preprint server for biology · 2025Article
- Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
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Authors and funding
39 authors.
Weilai DongDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0002-8376-1758
Sheng Chih JinLaboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.
Michael C SierantDepartment of Genetics, Yale School of Medicine, 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.
Qiongshi LuDepartment of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI 53706.ORCID 0000-0002-4514-0969
Sarah U MortonDivision of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115.ORCID 0000-0002-7816-2646
Junhui ZhangDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0003-0049-8032
Francesc López-GiráldezYale Center for Genome Analysis, Yale University, New Haven, CT 06516.ORCID 0000-0001-7476-9822
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.
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, Pennsylvania, 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.
James F CnotaDivision of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Michael WagnerDivision of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
Deepak SrivastavaGladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
Daniel BernsteinDepartment of Pediatrics, Cardiology, Stanford University, Stanford, CA 94304.ORCID 0000-0001-7761-5853
George A PorterDepartment of Pediatrics, The School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY 14642.ORCID 0000-0003-0726-9988
Jane NewburgerDepartment of Cardiology, Boston Children's Hospital, Boston, MA 02115.
Amy E RobertsDepartment of Cardiology, Boston Children's Hospital, 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.
Jonathan SeidmanDepartment of Genetics, Harvard Medical School, Boston, MA 02115.ORCID 0000-0002-9082-3566
Wendy K ChungDepartment of Pediatrics, Columbia University Medical Center, New York, NY 10032.ORCID 0000-0003-3438-5685
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
Richard P LiftonLaboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065.ORCID 0000-0002-5745-5984
Martina BruecknerDepartment of Genetics, Yale School of Medicine, New Haven, CT 06510.ORCID 0000-0003-0347-5389
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
$22.1MCTSA UM1 Program at University of UtahUM1TR004409 · NCATS · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI RACHEL HESS, Jennifer Juhl Majersik · 2023 to 2026
$21.9MYale Center for Mendelian DisordersU54HG006504 · NHGRI · YALE UNIVERSITY · PI GERSTEIN, MARK BENDER, GUNEL, MURAT · 2012 to 2015
$11.0MGenomic 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
$2.3MGenetics and genomics of congenital heart disease and associated neurodevelopmental abnormalitiesUM1HL098162 · NHLBI · YALE UNIVERSITY · PI BRUECKNER, MARTINA, GUPTA, ABHA RANI · 2015 to 2019
$2.2MBridging 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
$1.7MAmerican Heart Association (AHA) 19PRE34380842Children's Discovery Institute (CDI) CDI-FR-2021-926HHS | 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 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) RM1HG011014HHS | NIH | NHLBI | Division of Intramural Research (DIR) HL157653HHS | NIH | NHLBI | Division of Intramural Research (DIR) UO1-HL128711Howard Hughes Medical Institute (HHMI) Howard Hughes Medical InstituteHydrocephalus Association (HA) CTSA1405NCATS NIH HHS UL1 TR000003NCATS NIH HHS UM1 TR004409NHGRI 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 HL135680NHLBI NIH HHS UM1 HL098162NICHD NIH HHS R03 HD100883
Abstract
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in
Indexed as
Genes, RecessiveHeart Defects, CongenitalAnimalsConsanguinityExomeExome SequencingFemaleGenetic Predisposition to DiseaseGenotypeGrowth Differentiation Factor 1HumansMaleMicePedigreePhenotypeGDF1 protein, humanGrowth Differentiation Factor 1congenital heart diseaseexome-sequencinggenomicshuman genetics
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