Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease
Open accessAbstract
Importance: Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions. Objective: To compare the frequency of damaging variants in cancer risk genes among patients with CHD and control participants and identify associated clinical variables in patients with CHD who have cancer risk variants. Design, Setting, and Participants: This multicenter case-control study included participants with CHD who had previously been recruited to the Pediatric Cardiac Genomics Consortium based on presence of structural cardiac anomaly without genetic diagnosis at the time of enrollment. Permission to use published sequencing data from unaffected adult participants was obtained from 2 parent studies. Data were collected for this study from December 2010 to April 2019. Exposures: Presence of rare (allele frequency, <1 × 10-5) loss-of-function (LoF) variants in cancer risk genes. Main Outcomes and Measures: Frequency of LoF variants in cancer risk genes (defined in the Catalogue of Somatic Mutations in Cancer-Cancer Gene Consensus database), were statistically assessed by binomial tests in patients with CHD and control participants. Results: A total of 4443 individuals with CHD (mean [range] age, 13.0 [0-84] years; 2225 of 3771 with reported sex [59.0%] male) and 9808 control participants (mean [range] age, 52.1 [1-92] years; 4967 of 9808 [50.6%] male) were included. The frequency of LoF variants in regulatory cancer risk genes was significantly higher in patients with CHD than control participants (143 of 4443 [3.2%] vs 166 of 9808 [1.7%]; odds ratio [OR], 1.93 [95% CI, 1.54-2.42]; P = 1.38 × 10-12), and among CHD genes previously associated with cancer risk (58 of 4443 [1.3%] vs 18 of 9808 [0.18%]; OR, 7.2 [95% CI, 4.2-12.2]; P < 2.2 × 10-16). The LoF variants were also nominally increased in 14 constrained cancer risk genes with high expression in the developing heart. Seven of these genes (ARHGEF12, CTNNB1, LPP, MLLT4, PTEN, TCF12, and TFRC) harbored LoF variants in multiple patients with unexplained CHD. The highest rates for LoF variants in cancer risk genes occurred in patients with CHD and extracardiac anomalies (248 of 1482 individuals [16.7%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.59 [95% CI, 1.37-1.85]; P = 1.3 × 10-10) and/or neurodevelopmental delay (209 of 1393 individuals [15.0%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.40 [95% CI, 1.19-1.64]; P = 9.6 × 10-6). Conclusions and Relevance: Genotypes of CHD may account for increased cancer risks. In this cohort, damaging variants were prominent in the 216 genes that predominantly encode regulatory proteins. Consistent with their fundamental developmental functions, patients with CHD and damaging variants in these genes often had extracardiac manifestations. These data may also implicate cancer risk genes that are repeatedly varied in patients with unexplained CHD as CHD genes.
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A nonsense variant c.367C > T (p.Arg213Ter) in ABI1 was identified in a patient with cardiovascular dysfunction and neurodevelopmental disorder.
“A nonsense variant, c.367C > T, p.Arg213Ter, in ABI1 was identified in a patient with cardiovascular dysfunction and NDD135–137 (Table 2v).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [137]
The Results sections on candidate congenital-heart-disease genes and comorbid neurodevelopmental defects discuss loss-of-function variants in other genes, but do not identify an ABI1 variant or the patient described. Searches of our copy for “ABI1,” “c.367C > T,” and “Arg213Ter” found no matching passage. The cited paper therefore does not verify this specific case in our copy. (LLM, conf=0.76)
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Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Anderson, C. A. M., Arora, P., Avery, C. L., Baker-Smith, C. M., Beaton, A. Z., Boehme, A. K., Buxton, A. E., et al. (2023) · Circulation · doi:10.1161/cir.0000000000001123 · Cited by 8,300 · see citing works
The WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Morton, S. U., Shimamura, A., Newburger, P. E., Opotowsky, A. R., Quiat, D., Pereira, A. C., Jin, S. C., Gurvitz, M., Brueckner, M., Chung, W. K., Shen, Y., Bernstein, D., Gelb, B. D., Giardini, A., Goldmuntz, E., Kim, R. W., Lifton, R. P., Porter, G. A., Srivastava, D., Tristani-Firouzi, M., Newburger, J. W., Seidman, J. G., & Seidman, C. E.
- Affiliations
- Boston Children's Hospital (US)
- University of Massachusetts Chan Medical School (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Yale University (US)
- Columbia University Irving Medical Center (US)
- Stanford Medicine (US)
- Icahn School of Medicine at Mount Sinai (US)
- Cardiorespiratory Unit, Great Ormond Street Hospital, London, UK
- Children's Hospital of Philadelphia (US)
- Children's Hospital Los Angeles (US)
- Rockefeller University (US)
- Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, New York
- Gladstone Institutes (US)
- Division of Pediatric Cardiology, University of Utah, Salt Lake City
- Howard Hughes Medical Institute (US)
- Corresponding author
- Seidman, Christine E.
- ORCID
- Morton, Sarah U.
- Shimamura, Akiko
- Newburger, Peter E.
- Opotowsky, Alexander R.
- Quiat, Daniel
- Pereira, Alexandre C.
- Jin, Sheng Chih
- Gurvitz, Michelle
- Brueckner, Martina
- Chung, Wendy K.
- Shen, Yufeng
- Bernstein, Daniel
- Gelb, Bruce D.
- Goldmuntz, Elizabeth
- Kim, Richard W.
- Lifton, Richard P.
- Srivastava, Deepak
- Newburger, Jane W.
- Seidman, J. G.
- Seidman, Christine E.
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2021-04-01
- Volume
- 6
- Issue
- 4
- Pages
- 457
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC7578917
- OpenAlex
- W3094166859
- Cited by
- 62
- References
- 2
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 14 · 2023: 12 · 2022: 14 · 2021: 5 · 2020: 1
- FWCI
- 5.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Cardiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (UL1TR000003, UL1TR001863)
- National Heart, Lung, and Blood Institute (U01HL098153, U01HL098123, U01HL098162, R00HL143036, U01HL153009, UM1HL128761, U01HL098188, U01HL131003, U01HL098147, R01HL057181, T32HL007572, UM1HL172717)
- National Institute of General Medical Sciences (R01GM120609)
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- congenital heart disease, cancer risk genes, loss-of-function mutations, rare variants, cancer susceptibility, cancer surveillance, germline mutations, regulatory genes
- MeSH terms
- Loss of Function Mutation, Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Gene Expression Regulation, Gene Frequency, Heart Defects, Congenital, Humans, Infant, Infant, Newborn, Male, Middle Aged, Neoplasms, Genetic Variation, Case-Control Studies, Genetic Predisposition to Disease, Genes, Neoplasm, Young Adult
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