Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes

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 <i>MYH6</i> were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-03-24
DOI
https://doi.org/10.1073/pnas.2420343122
Citations
16
Primary Topic
Congenital heart defects research
Type
article
Field-Weighted Citation Impact
12.90

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article

Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes

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16 citations
Proceedings of the National Academy of Sciences
Congenital heart defects research
12.90
article

Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes

Deepak Srivastava, Martina K. Brueckner, Christine E. Seidman, Wei Jiang, Irina Tikhonova, Wendy K. Chung, Jonathan G. Seidman, Junyue Cao, Sarah U. Morton, J. William Gaynor, Weilai Dong, Carol Nelson‐Williams, Sheng Chih Jin, Richard D. Kim, Richard P. Lifton, Francesc López‐Giráldez, Yufeng Shen, Michael Wagner, Shrikant Mane, Kaya Bilgüvar, Jane W. Newburger, Amy E. Roberts, Daniel Bernstein, Martin Tristani‐Firouzi, George Arthur Porter Jr., Eileen King, Seema R. Mital, Stanley C. Sedore, Anna Giardini, Xue Zeng, Hongyu Zhao, Ziyu Lu, Michael C. Sierant, James Knight, Peter J. Gruber, H. Joseph Yost, Qiongshi Lu, Jungmin Choi, Bruce D. Gelb, Mark W. W. Russell, Junhui Zhang, Boyang Li, Elizabeth Goldmuntz, Monkol Lek, John Deanfield, Mark Yandell
article en
16 citations

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 <i>MYH6</i> were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.

Proceedings of the National Academy of SciencesVol. 122(13)
Broad Institute (US), Grand Rapids Community College (US), Cedars-Sinai Medical Center (US), Brigham and Women's Hospital (US), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), Gladstone Institutes (US), Children's Hospital of Philadelphia (US), University of Wisconsin–Madison (US), Harvard University (US), University of America (US), University of California, San Francisco (US), University of Toronto (CA), Korea University (KR), Washington University in St. Louis (US), University of Utah (US), University of Michigan (US), Columbia University Irving Medical Center (US), Great Ormond Street Hospital (GB), Hospital for Sick Children (CA), University of Rochester Medical Center (US), Acıbadem University (TR), Yale University (US), Child Health and Development Institute (US), SickKids Foundation (CA), Cedars-Sinai Smidt Heart Institute (US), Genetic Analysis (Norway) (NO), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), University College London (GB), University of Cincinnati (US), Massachusetts Institute of Technology (US), University of Pennsylvania (US), Rockefeller University (US), Catholic University of America (US), Michigan State University (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Howard Hughes Medical Institute, American Heart Association, Children's Discovery Institute, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Good health and well-being
Openalex Percentile: Top 1%
Congenital heart defects research
12.90
DOIOpen Access PDFOpenAlex
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