Scientific Sessions 2025  /  Young Hearts Early Career Investigator Award Competition  /  The Genetic Basis of Early Mortality in Neonates with Single Ventricle Disease: An NC-DEFINE Prospective Observational Cohort Study
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Final ID: 4344136

The Genetic Basis of Early Mortality in Neonates with Single Ventricle Disease: An NC-DEFINE Prospective Observational Cohort Study

Abstract Body (Do not enter title and authors here): Background: Single ventricle disease (SVD) is the most severe form of congenital heart disease. Despite surgical advances improving survival, heart failure (HF) remains a key contributor to early morbidity and mortality, especially in the first months of life. Defining genetic drivers of HF in SVD could enable early risk stratification and guide precision therapies to improve outcomes.

Hypothesis: Ultra-rare variants in genes associated with dilated cardiomyopathy (DCM) increase HF risk in neonates with SVD.

Approach: Neonates ≤21 days old with SVD were prospectively enrolled and followed at Duke (n=40). An additional 69 individuals (0.2–65y) from Duke and UNC formed an ambispective cohort. Chromosomal abnormalities were excluded. Ultra-rare (MAFAllofUs population.

Results: In the prospective cohort, 8 (20%) neonates developed severe HF, 11 (28%) developed MM HF, and 21 (52%) remained HF free, with mean follow-up of 2 years. Hosting a DCM-associated LP/P variant was linked to an 11-fold increased risk of severe HF (P=0.0009), while VUSs increased MM HF risk 6-fold (P=0.01). Most HF occurred within the first month. Findings were independently validated in the NCH cohort, where LP/P variants reduced freedom from severe HF (P=0.0007). Associations were attenuated in the ambispective cohort, suggesting survivor bias and underscoring the importance of early detection and risk stratification. Compared with the AllofUs cohort, the prospective cohort had a higher prevalence of LP/P variants (P<0.0001) but similar VUS burden, supporting a model in which LP/P variants drive primary disease risk, while low-penetrant variants may modify susceptibility in the context of SVD.

Conclusion: This study provides the first prospective evidence linking DCM-associated variants to significant risk for early-onset HF in SVD. These findings, independently validated in external cohorts, underscore the potential for genetic screening to inform early risk stratification and family counseling in this high-risk population.
  • Balint, Brittany  ( Duke University , Durham , North Carolina , United States )
  • Greskovich, Sarah  ( Nationwide Children's Hospital , Columbus , Ohio , United States )
  • Moreland, Blythe  ( Nationwide Children's Hospital , Columbus , Ohio , United States )
  • Gaither, Jeffrey  ( Nationwide Children's Hospital , Columbus , Ohio , United States )
  • Willoughby, Ava  ( Nationwide Children's Hospital , Columbus , Ohio , United States )
  • Bigelow, Amee  ( Nationwide Childrens Hospital , Columbus , Ohio , United States )
  • Mcbride, Kim  ( UCalgary , Calgary , Alberta , Canada )
  • Sunthankar, Sudeep  ( Vanderbilt , Nashville , Tennessee , United States )
  • Levin, Allison  ( Duke University Hospital , Mebane , North Carolina , United States )
  • Kurzlechner, Leonie  ( Duke University , Durham , North Carolina , United States )
  • Kreinbrook, Judah  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Monaco, Gabrielle  ( Duke University , Durham , North Carolina , United States )
  • Ebangwese, Santita  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Mitchell, Saige  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Srour, Meredith  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Yadav, Kanishk  ( Duke University , Durham , North Carolina , United States )
  • Neuerburg, Austin  ( UNC Children's , Chapel Hill , North Carolina , United States )
  • Farrell, Maureen  ( UNC Children's , Chapel Hill , North Carolina , United States )
  • Carlson, Katherine  ( Duke University , Durham , North Carolina , United States )
  • Sala, Angelina  ( Duke University , Durham , North Carolina , United States )
  • Girvin, Zachary  ( Vanderbilt , Nasvhille , Tennessee , United States )
  • Lancaster, Megan  ( Vanderbilt University Medical Cntr. , Nashville , Tennessee , United States )
  • Bair, Courtney  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Gangireddy, Srushti  ( VUMC , Mount Juliet , Tennessee , United States )
  • Jaworski, James  ( VUMC , Mount Juliet , Tennessee , United States )
  • Wei, Wei-qi  ( Vanderbilt University Medical Ctr , Nashville , Tennessee , United States )
  • Turek, Joseph  ( Duke University Medical Center , Durham , North Carolina , United States )
  • Leong, Martha Elisabeth  ( UNC Children's , Chapel Hill , North Carolina , United States )
  • Chiswell, Karen  ( Duke Clinical Research Institute , Durham , North Carolina , United States )
  • Allen, Andrew  ( Duke Clinical Research Institute , Durham , North Carolina , United States )
  • Li, Jennifer  ( Duke University Medical Center , Durham , North Carolina , United States )
  • Garg, Vidu  ( Nationwide Childrens Hospital , Columbus , Ohio , United States )
  • White, Peter  ( Nationwide Children's Hospital , Columbus , Ohio , United States )
  • Wolfe, Rachel  ( Duke University Hospital , Mebane , North Carolina , United States )
  • Kannankeril, Prince  ( VANDERBILT CHILDRENS HOSPITAL , Nashville , Tennessee , United States )
  • Hoffman, Timothy  ( UNC Children's , Chapel Hill , North Carolina , United States )
  • Landstrom, Andrew  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Dominguez Gonzalez, Carla  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Argueta Portillo, Cindy  ( Duke University , Durham , North Carolina , United States )
  • Mackenzie, Duncan  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Freedy, Katherine  ( Duke University School of Medicine , Durham , North Carolina , United States )
  • Onorato, Angela  ( Nationwide Childrens Hospital , Columbus , Ohio , United States )
    • Author Disclosures:
    Brittany Balint: DO NOT have relevant financial relationships | Sarah Greskovich: No Answer | Blythe Moreland: DO NOT have relevant financial relationships Ava Willoughby: DO NOT have relevant financial relationships | Amee Bigelow: No Answer | Kim McBride: No Answer | Sudeep Sunthankar: DO NOT have relevant financial relationships | Allison Levin: No Answer | Leonie Kurzlechner: DO NOT have relevant financial relationships | Judah Kreinbrook: DO NOT have relevant financial relationships | Gabrielle Monaco: DO NOT have relevant financial relationships | santita ebangwese: No Answer | Saige Mitchell: DO NOT have relevant financial relationships | Meredith Srour: DO NOT have relevant financial relationships | Kanishk Yadav: No Answer | Austin Neuerburg: DO NOT have relevant financial relationships | Maureen Farrell: No Answer | Katherine Carlson: DO NOT have relevant financial relationships | Angelina Sala: No Answer | Zachary Girvin: DO NOT have relevant financial relationships | Megan Lancaster: DO have relevant financial relationships ; Consultant:AltaThera Pharmaceuticals:Past (completed) ; Research Funding (PI or named investigator):NIH:Active (exists now) | Courtney Bair: No Answer | Srushti Gangireddy: No Answer | James Jaworski: No Answer | Wei-Qi Wei: No Answer | Joseph Turek: DO have relevant financial relationships ; Ownership Interest:Surge Ingenuity, Inc.:Active (exists now) | Martha Elisabeth Leong: DO NOT have relevant financial relationships | Karen Chiswell: DO NOT have relevant financial relationships | Andrew Allen: No Answer | Jennifer Li: No Answer | Vidu Garg: DO NOT have relevant financial relationships | Peter White: DO NOT have relevant financial relationships | Rachel Wolfe: DO NOT have relevant financial relationships | Prince Kannankeril: DO have relevant financial relationships ; Consultant:Solid Biosciences:Active (exists now) | Timothy Hoffman: DO NOT have relevant financial relationships | Andrew Landstrom: DO NOT have relevant financial relationships | Carla Dominguez Gonzalez: No Answer | Cindy Argueta Portillo: DO NOT have relevant financial relationships | Duncan MacKenzie: DO NOT have relevant financial relationships | Katherine Freedy: DO NOT have relevant financial relationships | Angela Onorato: DO NOT have relevant financial relationships
Meeting Info:

Scientific Sessions 2025

2025

New Orleans, Louisiana

Session Info:

Young Hearts Early Career Investigator Award Competition

Saturday, 11/08/2025 , 03:15PM - 04:30PM

Abstract Oral Session

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