De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease. (August 2020)

• Record Type: Journal Article
• Authors: 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.;
• Is Part Of: Circulation. Volume 13:Number 4(2020)
• Publication Date: 2020-08
• Subjects: genomics -- congenital heart disease -- heart transplantation -- mortality -- survival; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.119.002836
• Languages: English
• ISSNs: 2574-8300

Abstract

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. Abstract : Supplemental Digital Content is available in the text.