Alexander Alquiza

Background: Congenital heart diseases (CHDs) are irregularities in the structure or function of the heart that are present at birth and are a significant risk to children’s health. They are the most common congenital abnormalities and represent 1 out of every 3 major congenital problems.¹ Of these CHDs, ventricular septal defect (VSD), a hole between the two lower chambers of the heart, is the most common.² VSD was determined to be genetically heterogeneous, therefore, in the majority of patients, the genetic factors have yet to be specified.³ The MYH6 gene has been linked to causation of CHDs like VSD because it codes for the alpha heavy chain subunit belonging to cardiac myosin.² However, while the influence of the MYH6 gene on the heart’s development has been increasingly emphasized in research, the impact of its promoter’s variants is unknown.² Therefore, findings in this concentration can improve our understanding of the genetic basis of VSD formation.

Objective: The purpose of this study was to explore potential genetic mechanisms for the occurrence of VSD, especially focusing on the MYH6 gene, its variant promoters, and other closely associated genes.

Search Methods: The PubMed database was used to identify pertinent literature published between 2017 and 2023 using the following keywords: “congenital heart disease”, “ventricular septal defect”, “VSD”, “MYH6”, and “MYH6 gene”.

Results: Single nucleotide polymorphisms of the MYH6 gene have been shown to potentially be positively correlated with the incidence of CHD. For example, one study found a missense mutation in the MYH6 gene on the 14q11.2 chromosome in a patient with multiple cardiac defects, including VSD.² Another study found MYH6 to be one of the two highest-risk genes for VSD and cited one specific variation changing a Glutamine to Glutamic acid at exon 28.⁴ In a different study, two MYH6 gene promoter variants found only in VSD patients were observed to significantly reduce transcriptional activity.² Furthermore, these variants also altered binding of transcription factors resulting in inhibited differentiation of cardiac fibroblasts.² The TBX5 gene, a key component in the development of the layers of the heart and conduction system, was found to regulate several key genes heart development, including MYH6.⁵ A study found a Pro231Leu-mutant TBX5 gene was correlated with a sizable reduction in the transcriptional activity of the promoter for MYH6.⁵ Similarly, in a separate experiment, a heterozygous missense mutation involving a proline to threonine substitution was found to also decrease the transcription of the MYH6 promoter.³

Conclusions: Despite strides in research on the association between MYH6 and VSD, the exact mechanism behind VSD has not been defined. Establishing the connection between missense mutations of MYH6 promoters and VSD is a solid start, but causation needs to be proven and understood. This research has shown promise and suggests the potential for cheaper, earlier diagnosis through NGS. The relationship between MYH6 and TBX5 also presents an opportunity for improved analysis and personalized treatment of VSD.

Works Cited:

1. Zikarg YT, Yirdaw CT, Aragie TG. Prevalence of congenital septal defects among congenital heart defect patients in East Africa: A systematic review and meta-analysis. PLoS One. 2021;16(4):e0250006. Published 2021 Apr 22. doi:10.1371/journal.pone.0250006
2. 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
3. Chen HX, Zhang X, Hou HT, et al. Identification of a novel and functional mutation in the TBX5 gene in a patient by screening from 354 patients with isolated ventricular septal defect. Eur J Med Genet. 2017;60(7):385-390. doi:10.1016/j.ejmg.2017.04.011
4. Chaithra S, Agarwala S, Ramachandra NB. High-risk genes involved in common septal defects of congenital heart disease. Gene. 2022;840:146745. doi:10.1016/j.gene.2022.146745
5. Zhang Y, Sun YM, Xu YJ, et al. A New TBX5 Loss-of-Function Mutation Contributes to Congenital Heart Defect and Atrioventricular Block. Int Heart J. 2020;61(4):761-768. doi:10.1536/ihj.19-650