De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease

Marko T. Boskovski, Jason Homsy, Meena Nathan, Lynn A. Sleeper, Sarah Morton, Kathryn B. Manheimer, Angela Tai, Joshua Gorham, Matthew Lewis, Michael Swartz, George M. Alfieris, Emile A. Bacha, Mohsen Karimi, David Meyer, Khanh Nguyen, Daniel Bernstein, Angela Romano-Adesman, George A. Porter, Elizabeth Goldmuntz, Wendy K. ChungDeepak Srivastava, Jonathan R. Kaltman, Martin Tristani-Firouzi, Richard Lifton, Amy E. Roberts, J. William Gaynor, Bruce D. Gelb, Richard Kim, Jonathan G. Seidman, Martina Brueckner, John E. Mayer, Jane W. Newburger, Christine E. Seidman

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Background: De novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown. Methods: We studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network). Results: Two hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation. Conclusions: In patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Original languageEnglish
Pages (from-to)E002836
JournalCirculation. Genomic and precision medicine
Volume13
Issue number4
DOIs
StatePublished - 1 Aug 2020

Keywords

  • congenital heart disease
  • genomics
  • heart transplantation
  • mortality
  • survival

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