Genome sequencing is critical for forecasting outcomes following congenital cardiac surgery.

Journal: Nature communications
Published Date: Jul 10, 2025

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.

Authors

  • W Scott Watkins
    Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA.
  • Edgar J Hernandez
    Utah Center for Genetic Discovery, Department of Human Genetics, University of Utah Health, Salt Lake City, UT, USA.
  • Thomas A Miller
    Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
  • Nathan R Blue
    Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Utah Health, 30 N. Mario Capecchi Dr., Level 5 South, Salt Lake City, UT, 84132, USA. nblue1297@gmail.com.
  • Raquel Mae Zimmerman
    Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, 84108, USA.
  • Eric R Griffiths
    Pediatric Cardiothoracic Surgery, University of Utah, Salt Lake City, UT, USA.
  • Erwin Frise
    Fabric Genomics Inc., Oakland, CA, USA.
  • Daniel Bernstein
    Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Marko T Boskovski
    Department of Surgery, University of California, San Francisco, CA, 94143, USA.
  • Martina Brueckner
    Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06510, USA.
  • Wendy K Chung
    6 Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA.
  • J William Gaynor
    Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • Bruce D Gelb
    Mindich Child Health and Development Institute, Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, USA.
  • Elizabeth Goldmuntz
    Division of Cardiology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Peter J Gruber
    Division of Cardiac Surgery, Yale School of Medicine, New Haven, CT.
  • Jane W Newburger
    Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.
  • Amy E Roberts
    Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
  • Sarah U Morton
    Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • John E Mayer
    Department of Cardiovascular Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
  • Christine E Seidman
    Departments of Genetics and Medicine, Harvard Medical School, Boston, MA, 02115, USA.
  • Jonathan G Seidman
    Departments of Genetics and Medicine, Harvard Medical School, Boston, MA, 02115, USA.
  • Yufeng Shen
    Department of Systems Biology, Columbia University, New York, NY, USA. ys2411@cumc.columbia.edu.
  • Michael Wagner
  • H Joseph Yost
    Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.
  • Mark Yandell
    Eccles Institute of Human Genetics (M.Y.), University of Utah, Salt Lake City.
  • Martin Tristani-Firouzi
    Division of Pediatric Cardiology (M.T.-F.), University of Utah School of Medicine, Salt Lake City.

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