Genome sequencing is critical for forecasting outcomes following congenital cardiac surgery

W. Scott Watkins, Edgar J. Hernandez, Thomas A. Miller, Nathan R. Blue, Raquel Mae Zimmerman, Eric R. Griffiths, Erwin Frise, Daniel Bernstein, Marko T. Boskovski, Martina Brueckner, Wendy K. Chung, J. William Gaynor, Bruce D. Gelb, Elizabeth Goldmuntz, Peter J. Gruber, Jane W. Newburger, Amy E. Roberts, Sarah U. Morton, John E. Mayer, Christine E. Seidman, Jonathan G. Seidman, Yufeng Shen, Michael Wagner, H. Joseph Yost, Mark Yandell () and Martin Tristani-Firouzi ()
Additional contact information
W. Scott Watkins: University of Utah
Edgar J. Hernandez: University of Utah
Thomas A. Miller: Maine Medical Center
Nathan R. Blue: University of Utah
Raquel Mae Zimmerman: University of Utah
Eric R. Griffiths: University of Utah
Erwin Frise: Fabric Genomics Inc
Daniel Bernstein: Stanford University School of Medicine
Marko T. Boskovski: University of California
Martina Brueckner: Yale University School of Medicine
Wendy K. Chung: Harvard Medical School
J. William Gaynor: University of Pennsylvania
Bruce D. Gelb: Icahn School of Medicine at Mount Sinai
Elizabeth Goldmuntz: University of Pennsylvania
Peter J. Gruber: Yale University
Jane W. Newburger: Harvard Medical School
Amy E. Roberts: Harvard Medical School
Sarah U. Morton: Boston Children’s Hospital
John E. Mayer: Harvard Medical School
Christine E. Seidman: Harvard Medical School
Jonathan G. Seidman: Harvard Medical School
Yufeng Shen: Columbia University
Michael Wagner: Cincinnati Children’s Hospital Medical Center
H. Joseph Yost: University of Utah
Mark Yandell: University of Utah
Martin Tristani-Firouzi: and Division of Pediatric Cardiology

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract While exome and whole genome sequencing have transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we use artificial intelligence (AI) technologies to explore the predictive value of whole exome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a prospective observational cohort study of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes are associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes is further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes is also informative, reducing the risk for some adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Date: 2025
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DOI: 10.1038/s41467-025-61625-0

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