Talha Akram

Background: Congenital heart defects (CHDs) are the most common birth defects in the world¹. Tetralogy of Fallot (ToF) makes up 7-10% of CHD cases in the U.S., resulting in over 1,600 ToF cases annually according to the CDC². ToF does not have a cure, and 75% of infants with ToF will need corrective surgery within 3-6 months after birth. Most adults with the illness will need procedures later on to address valve issues and arrhythmias¹. While the cause of ToF is unknown, many studies have demonstrated that altered gene expression levels prenatally have been linked to its pathogenesis, many of which are caused by epigenetic modifications^3-6. These epigenetic modifications can be analyzed by clinicians so that a prenatal diagnosis of ToF can be made in order to tailor a treatment plan⁴.

Objective: In this narrative review, we examined studies highlighting differential gene expression patterns, their causes, and their effects on other genes in ToF patients with regards to cardiogenesis.

Search Methods: A search of the PubMed database was conducted with publications from 2017-2023 using the keywords “tetralogy of Fallot,” “diagnosis,” “embryology,” and “pathophysiology.”

Results: Multiple studies demonstrated that hyper- and hypomethylation of several genes were implicated in the development of ToF, whereas others had loss-of-function mutations, but ultimately gene expression levels in ToF patients were significantly different compared to healthy individuals^3-6. Genes such as NOTCH1, FLT4, and KDR, which are involved in cell differentiation and angiogenesis, were shown to have multiple loss-of-function mutation variants in ToF patients as compared to controls³. TBX20, a gene involved in the development of the endocardial cushions, was shown to have a hypomethylated promoter region in ToF patients, leading to gene overexpression and abnormal heart development⁵. A 2020 study highlighted differential methylation patterns in over 165 genetic loci in ToF infants as compared to healthy controls, further demonstrating a link to abnormal gene expression patterns⁴. The same 2020 study also noted how four genes, ARHGAP22, CDK5, TRIM27, and IER3, have a high predictive value for ToF diagnosis. These genes are well known to be involved in cardiogenesis, so a mutation affecting their expression levels could certainly lead to a CHD.

Conclusions: The literature suggests that many cases of ToF can be linked to inappropriate gene expression levels. These genes are often methylated or demethylated, one of several epigenetic phenomena, and result in altered product formation during cardiogenesis. As of now, it is unclear what causes these differential levels of methylation in utero, as well as other mutations which cause altered gene expression levels. However, by using these genes as biomarkers, clinicians can predict the likelihood that an infant will be born with ToF by studying their expression levels and epigenetic profiles.

Works Cited:

1. Forman J, Beech R, Slugantz L, Donnellan A. A Review of Tetralogy of Fallot and Postoperative Management. Crit Care Nurs Clin North Am. 2019;31(3):315-328. doi:10.1016/j.cnc.2019.05.003
2. Congenital heart defects – facts about tetralogy of Fallot. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/heartdefects/tetralogyoffallot.html. Published February 3, 2023. Accessed May 3, 2023.
3. Reuter MS, Chaturvedi RR, Jobling RK, et al. Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot. Circ Genom Precis Med. 2021;14(4):e003410. doi:10.1161/CIRCGEN.121.003410
4. Bahado-Singh R, Vishweswaraiah S, Mishra NK, Guda C, Radhakrishna U. Placental DNA methylation changes in detection of tetralogy of Fallot. Ultrasound Obstet Gynecol. 2020;55(6):768-775. doi:10.1002/uog.20292
5. Yang X, Kong Q, Li Z, Xu M, Cai Z, Zhao C. Association between the promoter methylation of the TBX20 gene and tetralogy of fallot. Scand Cardiovasc J. 2018;52(5):287-291. doi:10.1080/14017431.2018.1499955
6. Liu J, Wu Y, Sun H, et al. Association between placental DNA methylation and fetal congenital heart disease. Mol Genet Genomics. 2023;298(1):243-251. doi:10.1007/s00438-022-01944-9