Jiyeon Cha

Background: Ventricular Septal Defect (VSD), an aberrant development of the ventricular septum that leaves an opening between the ventricles, is the most common congenital heart defect.¹ Although most close spontaneously, large defects produce severe morbidity. The pathogenesis of VSD is also multifactorial, involving both genetic and predispositions and environmental factors, best exemplified by maternal dietary intake during gestation. Current studies highlight some genetic mutations and dietary factors that control VSD risk, thus pointing towards gaps in understanding the complex gene-environment interaction involved in cardiac development. These findings could suggest possible early prevention and directed intervention strategies.

Objective: In this narrative review, we explored some genetic mutations, namely in GATA4, GATA6, MYH6, and BHMT. These give rise to VSD pathogenesis and how maternal nutrition might influence these genetic hazards.

Search Methods: An online search in the PubMed database was conducted from 2017 to present using the following keywords: “Ventricular septal defect”, “congenital heart defect”, “GATA4 gene”, and “genetic mutation”.

Results: GATA4 mutations, and specifically the strongly conserved missence mutation Ser377Gly within the 3’-UTR, interfere with transcriptional activity and cause the production of aberrant cardiac transcripts.¹ This replacement of serine for glycine alters the polarity of the protein, its function and structure, and the secondary structure of the corresponding mRNA.¹ Sox7 and Sox18, downstream transcription factors of GATA4 compensate for GATA4 function, and their compromised activity is responsible for the defective regulation of early and late cardiogenic markers in mutated GATA4.^1,2 Similarly, GATA6 mutations at positions 452, 456, 466, 467, which significantly reduce protein solubility and enhance susceptibility to aggregation, interfering with septal formation.³ Compared to wild-type proteins, these mutations have lower average solubility scores, which indicate a higher tendency for pathological aggregation. Both GATA4 and GATA6 are central regulators in cardiac developmental networks, and their disturbance suppresses the expression of essential cardiogenic markers.³ Notably, MYH6 mutations cause weakening of myocardial contractility by inhibiting myosin and actin filament interaction and sarcomere assembly, which is necessary for normal heart muscle function and trabecular development.^4,5 Moreover, a polymorphism within the BHMT gene shows high gene-environment interaction: maternal bean consumption, which is rich in zinc and B vitamins, was shielding in offspring with specific BHMT variants.⁶ Conversely, maternal intake of fried, pickled, barbecued, or smoked foods was associated with an increased risk of VSD, while bean, egg, fruit, milk-dense diets and folate supplementation prenatally reduced risk substantially and suggest a possibly modifiable nutrition pathway to preventing VSD.⁶

Conclusions: The pathogenesis of VSD is influenced by a mix of genetic mutations and maternal dietary factors. Genes that play a role in cardiac morphogenesis, such as GATA4, GATA6, MYH6, and BHMT, play a critical role in the normal development of the heart, and their functions may be modulated by ntritional exposures during gestation. Such findings form the foundation of nutritional counseling for prenatal care and suggest that certain interventions reduce the incidence of congenital cardiac malformations.

Work Cited:

1. Khatami M, Ghorbani S, Adriani MR, et al. Novel point mutations in 3′-untranslated region of GATA4 gene are associated with sporadic non-syndromic atrial and ventricular septal defects. Curr Med Sci. 2022;42(2):129-143. doi:10.1007/s11596-021-2428-9
2. Afouda BA. Towards Understanding the Gene-Specific Roles of GATA Factors in Heart Development: Does GATA4 Lead the Way?. Int J Mol Sci. 2022;23(9):5255. Published 2022 May 9. doi:10.3390/ijms23095255
3. Hidayat T, Irwanto I, Rohman A, et al. Comprehensive in silico analysis of single nucleotide polymorphism and molecular dynamics simulation of human GATA6 protein in ventricular septal defect. Narra J. 2024;4(3):e1344. doi:10.52225/narra.v4i3.1344
4. Zuo JY, Chen HX, Liu ZG, Yang Q, He GW. Identification and functional analysis of variants of MYH6 gene promoter in isolated ventricular septal defects. BMC Med Genomics. 2022;15(1):213. Published 2022 Oct 8. doi:10.1186/s12920-022-01365-y
5. Marian AJ. Molecular Genetic Basis of Hypertrophic Cardiomyopathy. Circ Res. 2021;128(10):1533-1553. doi:10.1161/CIRCRESAHA.121.318346
6. Luo M, Wang T, Huang P, et al. Association and Interaction Effect of BHMT Gene Polymorphisms and Maternal Dietary Habits with Ventricular Septal Defect in Offspring. Nutrients. 2022;14(15):3094. Published 2022 Jul 28. doi:10.3390/nu14153094