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 Jr; Elizabeth Goldmuntz; Wendy K Chung; Deepak 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 Jr; Jane W Newburger; Christine E Seidman

doi:10.1161/CIRCGEN.119.002836

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

Circ Genom Precis Med. 2020 Aug;13(4):e002836. doi: 10.1161/CIRCGEN.119.002836. Epub 2020 Jun 30.

Authors

Marko T Boskovski^{1

2

3

4

5

6}, Jason Homsy⁶, Meena Nathan^{1

3}, Lynn A Sleeper^{2

4}, Sarah Morton^{7

6}, Kathryn B Manheimer⁸, Angela Tai⁶, Joshua Gorham⁶, Matthew Lewis⁹, Michael Swartz¹⁰, George M Alfieris¹⁰, Emile A Bacha¹¹, Mohsen Karimi¹², David Meyer¹³, Khanh Nguyen¹⁴, Daniel Bernstein¹⁵, Angela Romano-Adesman^{2

16}, George A Porter Jr¹⁷, Elizabeth Goldmuntz¹⁸, Wendy K Chung⁹, Deepak Srivastava^{19

20

21}, Jonathan R Kaltman²², Martin Tristani-Firouzi²³, Richard Lifton²⁴, Amy E Roberts⁴, J William Gaynor^{4

25}, Bruce D Gelb^{8

26

27}, Richard Kim²⁸, Jonathan G Seidman⁶, Martina Brueckner^{24

29}, John E Mayer Jr^{1

3}, Jane W Newburger², Christine E Seidman^{30

6

31}

Affiliations

¹ Department of Cardiac Surgery (M.T.B., M.N., J.E.M.), Harvard Medical School, MA.
² Department of Cardiology (M.T.B., L.A.S., A.E.R., J.W.N.), Harvard Medical School, MA.
³ Boston Children's Hospital and Department of Surgery (M.T.B., M.N., J.E.M.), Harvard Medical School, MA.
⁴ Department of Pediatrics (M.T.B., L.A.S., A.E.R., J.W.N.), Harvard Medical School, MA.
⁵ Division of Cardiac Surgery, Department of Surgery (M.T.B.), Harvard Medical School, MA.
⁶ Department of Genetics (M.T.B., J.H., S.M., A.T., J.G., J.G.S., C.E.S.), Harvard Medical School, MA.
⁷ Department of Newborn Medicine (S.M.), Harvard Medical School, MA.
⁸ Mindich Child Health and Development Institute (K.B.M., B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY.
⁹ Departments of Pediatrics and Medicine (M.L., W.K.C.), New York-Presbyterian Hospital/Columbia University Medical Center.
¹⁰ Department of Cardiac Surgery, University of Rochester, NY (M.S., G.M.A.).
¹¹ Division of Cardiac, Thoracic, and Vascular Surgery (E.A.B.), New York-Presbyterian Hospital/Columbia University Medical Center.
¹² Division of Cardiac Surgery (M.K.), Yale University School of Medicine, New Haven, CT.
¹³ Department of Pediatric Cardiothoracic Surgery (D.M.), Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park.
¹⁴ Pediatric Cardiac Surgery, Maria Fareri Children's Hospital, Valhalla, NY (K.N.).
¹⁵ Department of Pediatrics, Stanford University, CA (D.B.).
¹⁶ Department of Cardiology (A.R.-A.), Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park.
¹⁷ Department of Pediatrics, University of Rochester Medical Center, NY (G.A.P.).
¹⁸ Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia (E.G.).
¹⁹ Gladstone Institute of Cardiovascular Disease, San Francisco, CA (D.S.).
²⁰ Roddenberry Stem Cell Center at Gladstone, San Francisco, CA (D.S.).
²¹ Departments of Pediatrics and Biochemistry and Biophysics, University of California, San Francisco (D.S.).
²² Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, MD (J.R.K.).
²³ Department of Pediatrics, University of Utah Medical Center, Salt Lake City (M.T.-F.).
²⁴ Department of Genetics (R.L., M.B.), Yale University School of Medicine, New Haven, CT.
²⁵ Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, PA (J.W.G.).
²⁶ Department of Genetics and Genomic Sciences (B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY.
²⁷ Department of Pediatrics (B.D.G.), Icahn School of Medicine at Mount Sinai, New York, NY.
²⁸ Pediatric Cardiac Surgery, Children's Hospital of Los Angeles, CA (R.K.).
²⁹ Department of Pediatrics (M.B.), Yale University School of Medicine, New Haven, CT.
³⁰ Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital (C.E.S.), Harvard Medical School, MA.
³¹ Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.).

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.

Keywords: congenital heart disease; genomics; heart transplantation; mortality; survival.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Child
Child, Preschool
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 3
DNA Copy Number Variations*
Exome Sequencing
Female
Heart Defects, Congenital / genetics
Heart Defects, Congenital / mortality
Heart Defects, Congenital / pathology*
Heart Defects, Congenital / surgery
Heart Transplantation
Humans
Infant
Kaplan-Meier Estimate
Machine Learning
Male
Odds Ratio
Phenotype
Proportional Hazards Models

Associated data

ClinicalTrials.gov/NCT01196182

Abstract

Publication types

MeSH terms

Associated data

Grants and funding