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 Jr; Christine E Seidman; Jonathan G Seidman; Yufeng Shen; Michael Wagner; H Joseph Yost; Mark Yandell; Martin Tristani-Firouzi

doi:10.1038/s41467-025-61625-0

Genome sequencing is critical for forecasting outcomes following congenital cardiac surgery

Nat Commun. 2025 Jul 10;16(1):6365. doi: 10.1038/s41467-025-61625-0.

Authors

W Scott Watkins¹, Edgar J Hernandez², Thomas A Miller³, Nathan R Blue⁴, Raquel Mae Zimmerman², Eric R Griffiths⁵, Erwin Frise⁶, Daniel Bernstein⁷, Marko T Boskovski⁸, Martina Brueckner^{9

10}, Wendy K Chung¹¹, J William Gaynor¹², Bruce D Gelb¹³, Elizabeth Goldmuntz¹⁴, Peter J Gruber¹⁵, Jane W Newburger¹⁶, Amy E Roberts^{11

16}, Sarah U Morton¹⁷, John E Mayer Jr¹⁸, Christine E Seidman^{19

20}, Jonathan G Seidman¹⁹, Yufeng Shen²¹, Michael Wagner²², H Joseph Yost²³, Mark Yandell²⁴, Martin Tristani-Firouzi²⁵

Affiliations

¹ Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA.
² Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, 84108, USA.
³ Department of Pediatrics, Maine Medical Center, Portland, ME, USA.
⁴ Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, 84112, USA.
⁵ Pediatric Cardiothoracic Surgery, University of Utah, Salt Lake City, UT, USA.
⁶ Fabric Genomics Inc, Oakland, CA, 94612, USA.
⁷ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁸ Department of Surgery, University of California, San Francisco, CA, 94143, USA.
⁹ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06510, USA.
¹⁰ Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.
¹¹ Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹² Division of Cardiothoracic Surgery, Department of Surgery, Children's Hospital of Philadelphia, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
¹⁴ Division of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Department of Surgery, Yale University, New Haven, CT, USA.
¹⁶ Department of Cardiology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
¹⁷ Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, MA, USA.
¹⁸ Department of Cardiovascular Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹⁹ Departments of Genetics and Medicine, Harvard Medical School, Boston, MA, 02115, USA.
²⁰ Cardiovascular Division, Massachusetts General Brigham, Boston, MA, 02115, USA.
²¹ Departments of Systems Biology and Biomedical Informatics, Columbia University, New York, NY, 10032, USA.
²² Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
²³ Molecular Medicine Program, University of Utah, Salt Lake City, UT, 84112, USA.
²⁴ Department of Human Genetics, University of Utah, Salt Lake City, UT, 84112, USA. myandell@genetics.utah.edu.
²⁵ Nora Eccles Harrison Cardiovascular Research and Training Institute, and Division of Pediatric Cardiology, Salt Lake City, UT, 84108, USA. Martin.Tristani@utah.edu.

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.

Publication types

Observational Study

MeSH terms

Cardiac Surgical Procedures* / adverse effects
Child
Child, Preschool
Exome Sequencing
Female
Forecasting
Genotype
Heart Defects, Congenital* / genetics
Heart Defects, Congenital* / mortality
Heart Defects, Congenital* / surgery
Humans
Infant
Infant, Newborn
Male
Prospective Studies
Treatment Outcome
Whole Genome Sequencing*

Abstract

Publication types

MeSH terms

Grants and funding