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

• 成果类型: Article
• 署名作者: Sierant, Michael C.; Jin, Sheng Chih; Bilguvar, Kaya; Morton, Sarah U.; Dong, Weilai; Jiang, Wei; Lu, Ziyu; Li, Boyang; Lopez-Giraldez, Francesc; Tikhonova, Irina; Zeng, Xue; Lu, Qiongshi; Choi, Jungmin; Zhang, Junhui; Nelson-Williams, Carol; Knight, James R.; Zhao, Hongyu; Cao, Junyue; Mane, Shrikant; Sedore, Stanley C.; Gruber, Peter J.; Lek, Monkol; Goldmuntz, Elizabeth; Deanfield, John; Giardini, Alessandro; Mital, Seema; Russell, Mark; Gaynor, J. William; King, Eileen; Wagner, Michael; Srivastava, Deepak; Shen, Yufeng; Bernstein, Daniel; Porter Jr, George A.; Newburger, Jane W.; Seidman, Jonathan G.; Roberts, Amy E.; Yandell, Mark; Yost, H. Joseph; Tristani-Firouzi, Martin; Kim, Richard; Chung, Wendy K.; Gelb, Bruce D.; Seidman, Christine E.; Brueckner, Martina; Lifton, Richard P.
• 署名单位: Yale University; Rockefeller University; Washington University (WUSTL); Washington University (WUSTL); Yale University; Yale University; Yale University; Acibadem University; Acibadem University; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Yale University; Rockefeller University; University of Wisconsin System; University of Wisconsin Madison; Korea University; Korea University Medicine (KU Medicine); Yale University; Michigan State University; Michigan State University College of Human Medicine; Yale University; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of London; University College London; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of Toronto; Hospital for Sick Children (SickKids); University of Michigan System; University of Michigan; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University System of Ohio; University of Cincinnati; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; Columbia University; NewYork-Presbyterian Hospital; Columbia University; NewYork-Presbyterian Hospital; Stanford University; University of Rochester; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Utah System of Higher Education; University of Utah; Catholic University of America; Utah System of Higher Education; University of Utah; Cedars Sinai Medical Center; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Columbia University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15045
• DOI: 10.1073/pnas.2420343122
• 发表日期: 2025-04-01
• 关键词: molecular inversion probes; de-novo mutations; wide association; noonan-syndrome; defects; protein; DISCOVERY; FRAMEWORK; mosaicism; variants

摘要

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 MYH6 were enriched in multiple CHD phenotypes and account for similar to 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.