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Genome sequencing is critical for forecasting outcomes following congenital cardiac surgery

Author

Listed:
  • 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
    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
    Harvard Medical School)

  • Sarah U. Morton

    (Boston Children’s Hospital)

  • John E. Mayer

    (Harvard Medical School)

  • Christine E. Seidman

    (Harvard Medical School
    Massachusetts General Brigham)

  • 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)

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.

Suggested Citation

  • 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, 2025. "Genome sequencing is critical for forecasting outcomes following congenital cardiac surgery," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61625-0
    DOI: 10.1038/s41467-025-61625-0
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    References listed on IDEAS

    as
    1. W. Scott Watkins & E. Javier Hernandez & Sergiusz Wesolowski & Brent W. Bisgrove & Ryan T. Sunderland & Edwin Lin & Gordon Lemmon & Bradley L. Demarest & Thomas A. Miller & Daniel Bernstein & Martina , 2019. "De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Højsgaard, Søren, 2012. "Graphical Independence Networks with the gRain Package for R," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 46(i10).
    3. You Li & Nikolai T. Klena & George C. Gabriel & Xiaoqin Liu & Andrew J. Kim & Kristi Lemke & Yu Chen & Bishwanath Chatterjee & William Devine & Rama Rao Damerla & Chienfu Chang & Hisato Yagi & Jovenal, 2015. "Global genetic analysis in mice unveils central role for cilia in congenital heart disease," Nature, Nature, vol. 521(7553), pages 520-524, May.
    4. Samir Zaidi & Murim Choi & Hiroko Wakimoto & Lijiang Ma & Jianming Jiang & John D. Overton & Angela Romano-Adesman & Robert D. Bjornson & Roger E. Breitbart & Kerry K. Brown & Nicholas J. Carriero & Y, 2013. "De novo mutations in histone-modifying genes in congenital heart disease," Nature, Nature, vol. 498(7453), pages 220-223, June.
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