Genetic and clinical variables act synergistically to impact neurodevelopmental outcomes in children with single ventricle heart disease

Authors

Thomas Miller, Maine Medical CenterFollow
Edgar J. Hernandez, Department of Human Genetics and Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA.
J William Gaynor, Department of Surgery, Children's Hospital of Philadelphia, and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Mark W. Russell, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
Jane W. Newburger, Department of Cardiology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Wendy Chung, Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA.
Elizabeth Goldmuntz, Division of Cardiology, Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
James F. Cnota, Heart Institute, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Document Type

Article

Publication Date

9-27-2023

Institution/Department

Pediatrics

Journal Title

Communications medicine

Abstract

BACKGROUND: Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetics are complicated by the intrinsic severity of the CHD lesion and interactions with conditionally dependent clinical variables. METHODS: Bayesian Networks were applied to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD. RESULTS: As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increase the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables act synergistically to further increase the probability of a low MDI score by 10-fold. The absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increase the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increase the probability of a good outcome by 59-fold. CONCLUSIONS: Our analyses suggest a modest genetic contribution to neurodevelopmental outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.

First Page

127

Recommended Citation

Miller TA, Hernandez EJ, Gaynor JW, et al. Genetic and clinical variables act synergistically to impact neurodevelopmental outcomes in children with single ventricle heart disease. Commun Med (Lond). 2023;3(1):127. Published 2023 Sep 27. doi:10.1038/s43856-023-00361-2