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

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


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.


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).


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.


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: Unique identifier: NCT01196182.

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