My Lai

Background: Tetralogy of Fallot is the one of the most common cyanotic congenital heart diseases, affecting 3 out of 10,000 infants yearly.¹ Tetralogy of Fallot (TOF) features 4 significant hallmarks, including ventricular septal defect (VSD), aorta overriding VSD, pulmonary stenosis, and right ventricular hypertrophy. ^2,3 Current successful treatment requires early corrective surgical repair, including patch closure of VSD and transannular patch insertion to enlarge the pulmonary stenosis; however, while the mortality rate post-surgery is less than 1%, there is an increasing risk of pulmonary regurgitation and sudden cardiac death when patients reach adulthood.^4,5,6 Syndromic TOF patients, including those associated with a known genetic syndrome such as Trisomy 21 or DiGeorge, accounts for 20% of the TOF cases while non-syndromic patients (no etiology cause) accounts for the majority. Current diagnosis includes prenatal screening (ultrasound, fetal echocardiogram) and Chest-Xray, but it is beneficial to find a genetic correlation for patients predisposed to TOF. While there is no known monogenic mechanism, impaired signaling molecules in cardiac cell development is recognized as a promising field of research. NOTCH1 signaling is a key player in regulating cell determination and proliferation, thus mutations in NOTCH1 signaling genes suggest cardiac anomalies such as bicuspid aortic valve or defective outflow track in Tetralogy of Fallot.

Objective: This narrative review considers recent studies on the mechanism of NOTCH1 signaling gene mutations in cardiac cell development that manifest congenital heart defects in Tetralogy of Fallot.

Search Methods: Using the PubMed database limited from 2017 to 2023, the following search terms were used: “Tetralogy of Fallot”, “NOTCH1”, “NOTCH1 missense”, “cardiac signaling genes”.

Results: Studies suggested important roles of NOTCH1 signaling genes in regulating cardiac cell development and proliferation. Extensive Whole Genome Sequencing was performed to illustrate NOTCH1 genes have the highest number of deleterious, unique variants compared to other genes in non-syndromic patients with TOF, including 24 in-frame indels and missense variants with an additional 7 loss of function mutations.⁹ Ultra-rare missense NOTCH1 variants were suspected to frequently alternate the disulfide bonds forming by conserved cysteine residues in NOTCH1 extracellular domain. ⁸ One of the mutations, C607N, impaired S1 cleavage, an important step in NOTCH1 receptor maturation leading to loss of protein function.⁹ In addition, p.N1875S variant significantly reduced NOTCH1 signaling in the presence of JAG1 (a common ligand).⁹ Down-regulating NOTCH1 decreases early cardiomyocyte mitosis and proliferation, specifically for human ventricular-like cardiomyocytes.⁷

Conclusion: NOTCH1 signaling genes regulate cell-to-cell communication  and cardiomyocyte development. Therefore, a potential genetic etiology for TOF proposed the impact of rare missense mutations in down-regulating NOTCH1 signaling genes, leading to a decrease in cardiomyocyte division. Consideration of increasing the rate of cardiomyocyte division and control right ventricular hypertrophy using beta-blockers, such as propranolol, to decrease wall stress can be a promising treatment management along with surgery.

Works Cited:

1. Althali NJ, Hentges KE. Genetic insights into non-syndromic Tetralogy of Fallot. Front Physiol. 2022;13:1012665. Published 2022 Oct 6. doi:10.3389/fphys.2022.1012665
2. Morgenthau A, Frishman WH. Genetic Origins of Tetralogy of Fallot. Cardiol Rev. 2018;26(2):86-92. doi:10.1097/CRD.0000000000000170
3. Lim TB, Foo SYR, Chen CK. The Role of Epigenetics in Congenital Heart Disease. Genes (Basel). 2021;12(3):390. Published 2021 Mar 9. doi:10.3390/genes12030390
4. Bedair R, Iriart X. EDUCATIONAL SERIES IN CONGENITAL HEART DISEASE: Tetralogy of Fallot: diagnosis to long-term follow-up. Echo Res Pract. 2019;6(1):R9-R23. doi:10.1530/ERP-18-0049
5. van der Ven JPG, van den Bosch E, Bogers AJCC, Helbing WA. Current outcomes and treatment of tetralogy of Fallot. F1000Res. 2019;8:F1000 Faculty Rev-1530. Published 2019 Aug 29. doi:10.12688/f1000research.17174.1
6. Jacobs JP, Mayer JE Jr, Pasquali SK, et al. The Society of Thoracic Surgeons Congenital Heart Surgery Database: 2018 Update on Outcomes and Quality. Ann Thorac Surg. 2018;105(3):680-689. doi:10.1016/j.athoracsur.2018.01.001
7. Ye S, Wang C, Xu Z, et al. Impaired Human Cardiac Cell Development due to NOTCH1 Deficiency. Circ Res. 2023;132(2):187-204. doi:10.1161/CIRCRESAHA.122.321398
8. Manshaei R, Merico D, Reuter MS, et al. Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences. Front Genet. 2020;11:957. Published 2020 Sep 15. doi:10.3389/fgene.2020.00957
9. Page DJ, Miossec MJ, Williams SG, et al. Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot. Circ Res. 2019;124(4):553-563. doi:10.1161/CIRCRESAHA.118.313250