Journal article
De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease
Circulation. Genomic and precision medicine, Vol.13(4), pp.e002836-e002836
08/01/2020
DOI: 10.1161/CIRCGEN.119.002836
PMCID: PMC7439931
PMID: 32812804
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.
Details
- Title: Subtitle
- De Novo Damaging Variants, Clinical Phenotypes, and Post-Operative Outcomes in Congenital Heart Disease
- Creators
- Marko T. Boskovski - Harvard UniversityJason Homsy - Harvard UniversityMeena Nathan - Boston Children's HospitalLynn A. Sleeper - Harvard UniversitySarah Morton - Harvard UniversityKathryn B. Manheimer - Child Health and Development InstituteAngela Tai - Harvard UniversityJoshua Gorham - Harvard UniversityMatthew Lewis - Columbia University Irving Medical CenterMichael Swartz - University of RochesterGeorge M. Alfieris - University of RochesterEmile A. Bacha - New York Hospital QueensMohsen Karimi - Yale UniversityDavid Meyer - Cohen Children's Medical CenterKhanh Nguyen - Maria Fareri Children's HospitalDaniel Bernstein - Stanford UniversityAngela Romano-Adesman - Harvard UniversityGeorge A. Porter - University of Rochester Medical CenterElizabeth Goldmuntz - University of PennsylvaniaWendy K. Chung - Columbia University Irving Medical CenterDeepak Srivastava - Gladstone InstitutesJonathan R. Kaltman - National Heart Lung and Blood InstituteMartin Tristani-Firouzi - University of UtahRichard Lifton - Yale UniversityAmy E. Roberts - Harvard UniversityJ. William Gaynor - Children's Hospital of PhiladelphiaBruce D. Gelb - Child Health and Development InstituteRichard Kim - Children's Hospital of Los AngelesJonathan G. Seidman - Harvard UniversityMartina Brueckner - Yale UniversityJohn E. Mayer - Boston Children's HospitalJane W. Newburger - Harvard UniversityChristine E. Seidman - Brigham and Women's Hospital
- Resource Type
- Journal article
- Publication Details
- Circulation. Genomic and precision medicine, Vol.13(4), pp.e002836-e002836
- DOI
- 10.1161/CIRCGEN.119.002836
- PMID
- 32812804
- PMCID
- PMC7439931
- NLM abbreviation
- Circ Genom Precis Med
- ISSN
- 2574-8300
- eISSN
- 2574-8300
- Publisher
- Lippincott Williams & Wilkins
- Language
- English
- Date published
- 08/01/2020
- Academic Unit
- Cardiothoracic Surgery
- Record Identifier
- 9984557845102771
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