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

doi:10.1161/CIRCGEN.119.002836

. 2020 Aug;13(4):e002836.

doi: 10.1161/CIRCGEN.119.002836. Epub 2020 Jun 30.

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

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.).

PMID: 32812804
PMCID: PMC7439931
DOI: 10.1161/CIRCGEN.119.002836

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

Marko T Boskovski et al. Circ Genom Precis Med. 2020 Aug.

. 2020 Aug;13(4):e002836.

doi: 10.1161/CIRCGEN.119.002836. Epub 2020 Jun 30.

Authors

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.).

PMID: 32812804
PMCID: PMC7439931
DOI: 10.1161/CIRCGEN.119.002836

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.

PubMed Disclaimer

Conflict of interest statement

None.

Figures

**Figure 1.**
**Description of study population.** A, Flow chart depicting the derivation of the study population. B, Comparison of patients with and without available surgical data. Surgical data were not available for patients who underwent surgery before the treatment center began collecting data. Damaging genic variants (DGVs) include only those that are clinically significant (occur in multi-hit genes; see Methods in the Data Supplement). DND indicates de novo damaging.

**Figure 2.**
Kaplan-Meier curves depicting (A) time to death or heart transplantation following first open-heart surgery and (B) time to final extubation following open-heart surgery for congenital heart disease patients with and without de novo damaging variants (includes only clinically significant damaging genic variants [DGVs]). Adjusted hazard ratios (HR) are shown.

**Figure 3.**
**Interaction between de novo damaging variants and extra-cardiac anomalies (ECA) in their association with transplant-free survival and time to final extubation.** A, Models for transplant-free survival and time to final extubation that include interaction between DND variants and ECAs. Analyses include only clinically significant damaging genic variants (DGVs). There was a significant interaction between the 2 for transplant-free survival. Among patients without ECAs, de novo damaging variants were associated with worse transplant-free survival, but there was no significant association among patients with ECAs. For time to final extubation, both de novo damaging variants and ECAs were independently associated with worse outcome without interaction between the 2. B and C, Kaplan-Meier curves depicting time to death or heart transplantation following first open-heart surgery for patients with and without ECAs. Adjusted hazard ratios (HR) are shown. STAT indicates Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery.

**Figure 4.**
**Identification and validation of high-risk de novo damaging variants.** Permutation analyses identified de novo copy number variants at 15q25.2 and 15q11.2 as high-risk for transplant-free survival (A) and 15q25.2, 22q11.21, and 3p25.1-26.3 as high-risk for prolonged time to final extubation (B). C, Kaplan-Meier curves depicting time to death or heart transplantation after first open-heart surgery in congenital heart disease (CHD) patients with high-risk de novo damaging variants (15q25.2 and 15q11.2), any other de novo damaging variants, and no de novo variants. D, Kaplan-Meier curves depicting time to final extubation after open-heart surgery in patients with high-risk de novo damaging variants (15q25.2, 22q11.21, and 3p25.1-26.3), other de novo damaging variants and no de novo variants. Adjusted hazard ratios (HR) are shown.

See this image and copyright information in PMC

Cited by

Early ascertainment of genetic diagnoses clarifies impact on medium-term survival following neonatal congenital heart surgery.
Landis BJ, Helm BM, Durbin MD, Helvaty LR, Herrmann JL, Johansen M, Geddes GC, Ware SM. Landis BJ, et al. J Clin Invest. 2024 Jul 30;134(18):e180098. doi: 10.1172/JCI180098. J Clin Invest. 2024. PMID: 39078715 Free PMC article. No abstract available.
How Will Artificial Intelligence Shape the Future of Decision-Making in Congenital Heart Disease?
Pozza A, Zanella L, Castaldi B, Di Salvo G. Pozza A, et al. J Clin Med. 2024 May 20;13(10):2996. doi: 10.3390/jcm13102996. J Clin Med. 2024. PMID: 38792537 Free PMC article. Review.
Using novel data linkage of congenital heart disease biobank data with administrative health data to identify cardiovascular outcomes to inform genomic analysis.
Lain SJ, Blue GM, O'Malley BR, Winlaw DS, Sholler G, Dunwoodie SL, Nassar N; Congenital Heart Disease Synergy Study group. Lain SJ, et al. Int J Popul Data Sci. 2023 Nov 14;8(1):2150. doi: 10.23889/ijpds.v8i1.2150. eCollection 2023. Int J Popul Data Sci. 2023. PMID: 38414539 Free PMC article.
In-Depth Genomic Analysis: The New Challenge in Congenital Heart Disease.
Nappi F. Nappi F. Int J Mol Sci. 2024 Feb 1;25(3):1734. doi: 10.3390/ijms25031734. Int J Mol Sci. 2024. PMID: 38339013 Free PMC article. Review.
Clinically Relevant Genetic Considerations for Patients With Tetralogy of Fallot.
Bassett AS, Reuter MS, Malecki S, Silversides C, Oechslin E. Bassett AS, et al. CJC Pediatr Congenit Heart Dis. 2023 Oct 10;2(6Part A):426-439. doi: 10.1016/j.cjcpc.2023.10.002. eCollection 2023 Dec. CJC Pediatr Congenit Heart Dis. 2023. PMID: 38161665 Free PMC article. Review.

See all "Cited by" articles

References

1. Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr. 2008;153:807–813. doi: 10.1016/j.jpeds.2008.05.059. - PMC - PubMed
1. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:2241–2247. doi: 10.1016/j.jacc.2011.08.025. - PubMed
1. Matthews TJ, MacDorman MF. Infant mortality statistics from the 2010 period linked birth/infant death data set. Natl Vital Stat Rep. 2013;62:1–26. - PubMed
1. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350:1262–1266. doi: 10.1126/science.aac9396. - PMC - PubMed
1. Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498:220–223. doi: 10.1038/nature12141. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

[1] Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr. 2008;153:807–813. doi: 10.1016/j.jpeds.2008.05.059. - PMC - PubMed

[2] Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr. 2008;153:807–813. doi: 10.1016/j.jpeds.2008.05.059. - PMC - PubMed

[3] van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:2241–2247. doi: 10.1016/j.jacc.2011.08.025. - PubMed

[4] van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, Roos-Hesselink JW. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:2241–2247. doi: 10.1016/j.jacc.2011.08.025. - PubMed

[5] Matthews TJ, MacDorman MF. Infant mortality statistics from the 2010 period linked birth/infant death data set. Natl Vital Stat Rep. 2013;62:1–26. - PubMed

[6] Matthews TJ, MacDorman MF. Infant mortality statistics from the 2010 period linked birth/infant death data set. Natl Vital Stat Rep. 2013;62:1–26. - PubMed

[7] Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350:1262–1266. doi: 10.1126/science.aac9396. - PMC - PubMed

[8] Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, et al. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science. 2015;350:1262–1266. doi: 10.1126/science.aac9396. - PMC - PubMed

[9] Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498:220–223. doi: 10.1038/nature12141. - PMC - PubMed

[10] Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, Romano-Adesman A, Bjornson RD, Breitbart RE, Brown KK, et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013;498:220–223. doi: 10.1038/nature12141. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Associated data

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials