Majed Alsulami¹*, Mahmood Rasool² and Isam M Abu Zeid^1,3,4

¹Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
²Institute of Genomic Medicine Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
³Centre of Excellence in Bionanoscience, King Abdulaziz University, Jeddah, Saudi Arabia
⁴Princess Doctor Najla Bint Saud Al Saud Distinguished Research Center for Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia

*Corresponding Author: Majed Alsulami, Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.

Received: February 25, 2025; Published: February 28, 2025

Abstract

Congenital heart diseases (CHDs) arise from anatomical abnormalities in the heart and major blood vessels during fetal development, significantly impacting morbidity and mortality rates globally. Key genes play crucial roles in cardiogenesis and the pathogenesis of CHD. Notable among these are NKX2-5, GATA4, TBX1, TBX5, and KDM6A. NKX2-5 is essential for cardiac morphogenesis and is linked to various defects, including atrial septal defects. GATA4 acts as a powerful activator of cardiac genes and works in conjunction with NKX2-5 to initiate cardiogenesis; variants in this gene are associated with multiple CHDs. TBX1 and TBX5 are critical for proper cardiovascular development, with mutations resulting in significant phenotypes characteristic of specific syndromes. KDM6A, a histone demethylase, regulates gene expression during embryonic development and is implicated in CHD through its role in essential signaling pathways. Understanding these genes enhances the knowledge of CHD mechanisms, paving the way for personalized treatment strategies and improved clinical outcomes. Continued research into the genetic basis of CHD is vital for developing effective interventions and providing better genetic counseling for affected families.

Keywords: Congenital heart diseases (CHDs); RNA; GATA4

References

1. Rao P Syamasundar. "Recent Advances in the Diagnosis and Management of Congenital Heart Disease”. Children1 (2024): 84.‏
2. Saxena Anita. "Congenital heart disease in India: A status report”. Indian Pediatrics55 (2018): 1075-1082.‏
3. Wood Kathleen P., et al. "Evaluation and care of common pediatric cardiac disorders”. (2023): 576-599.‏
4. Netala Vasudeva Reddy., et al. "A comprehensive review of cardiovascular disease management: cardiac biomarkers, imaging modalities, pharmacotherapy, surgical interventions, and herbal remedies”. Cells17 (2024): 1471.‏
5. Wu Yue., et al. "Genetic and epigenetic mechanisms in the development of congenital heart diseases”. World Journal of Pediatric Surgery2 (2021): e000196.‏
6. Yasuhara Jun and Vidu Garg. "Genetics of congenital heart disease: a narrative review of recent advances and clinical implications”. Translational Pediatrics9 (2021): 2366.‏
7. Chhatwal Karanjot., et al. "Uncovering the genetic basis of congenital heart disease: recent advancements and implications for clinical management”. CJC Pediatric and Congenital Heart Disease6 (2023): 464-480.‏
8. Lannering Katarina., et al. "Screening for critical congenital heart defects in Sweden”. Pediatrics4 (2023): e2023061949.‏
9. Mackie Andrew S., et al. "Cost of congenital heart disease hospitalizations in Canada: a population-based study”. Canadian Journal of Cardiology6 (2017): 792-798.‏
10. Bragança José., et al. "Charting the path: navigating embryonic development to potentially safeguard against congenital heart defects”. Journal of Personalized Medicine8 (2023): 1263.‏
11. Chang Chi-Son., et al. "Prevalence of associated extracardiac anomalies in prenatally diagnosed congenital heart diseases”. PLoS One3 (2021): e0248894.‏
12. Tan Meihua., et al. "Genetic diagnostic yield and novel causal genes of congenital heart disease”. Frontiers in Genetics13 (2022): 941364.‏
13. McMillan W Owen., et al. "From patterning genes to process: unraveling the gene regulatory networks that pattern Heliconius wings”. Frontiers in Ecology and Evolution8 (2020): 221.‏
14. Edwards Moriah., et al. "Genetic investigation and diagnosis in adults with congenital heart disease with or without structural or neurodevelopmental comorbidity: a retrospective chart review”. Frontiers in Genetics15 (2024): 1412806.‏
15. Kalisch-Smith., et al. "Environmental risk factors for congenital heart disease”. Cold Spring Harbor Perspectives in Biology3 (2020): a037234.‏
16. Li Yan-Jie and Yi-Qing Yang. "An update on the molecular diagnosis of congenital heart disease: focus on loss-of-function mutations”. Expert Review of Molecular Diagnostics4 (2017): 393-401.‏
17. Hartman Robert J., et al. "The contribution of chromosomal abnormalities to congenital heart defects: a population-based study”. Pediatric Cardiology32 (2011): 1147-1157.‏
18. Glessner Joseph T., et al. “Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data”. Circulation Research10 (2014): 884-896.
19. Homsy Jason., et al. "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies”. Science6265 (2015): 1262-1266.
20. Bull Marilyn J. “Down Syndrome”. The New England Journal of Medicine24 (2020): 2344-2352.
21. Gravholt Claus H., et al. "Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting”. European Journal of Endocrinology3 (2017): G1-G70.‏
22. Mlynarski Elisabeth E., et al. "Rare copy number variants and congenital heart defects in the 22q11. 2 deletion syndrome”. Human Genetics135 (2016): 273-285.‏
23. Battaglia Agatino., et al. "Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation”. Pediatrics2 (2008): 404-410.‏
24. Pober Barbara R. "williams–Beuren syndrome”. New England Journal of Medicine3 (2010): 239-252.‏
25. McDermott Deborah A., et al. "TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome”. Pediatric Research5 (2005): 981-986.‏
26. Sperling Silke., et al. "Identification and functional analysis of CITED2 mutations in patients with congenital heart defects”. Human Mutation6 (2005): 575-582.
27. Posch Maximilian G., et al. "Mutations in GATA4, NKX2. 5, CRELD1, and BMP4 are infrequently found in patients with congenital cardiac septal defects”. American journal of medical genetics Part A2 (2008): 251-253.‏ ‏
28. Smemo Scott., et al. "Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease”. Human Molecular Genetics14 (2012): 3255-3263.‏
29. Ferese Rosangela., et al. "Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect”. Human Mutation10 (2018): 1428-1441.‏
30. Smith Kelly A., et al. "Dominant-negative ALK2 allele associates with congenital heart defects”. Circulation24 (2009): 3062-3069.‏
31. Reamon‐Buettner., et al. "HEY2 mutations in malformed hearts”. Human Mutation1 (2006): 118-118.‏
32. Kerstjens-Frederikse Wilhelmina S., et al. "Cardiovascular malformations caused by NOTCH1 mutations do not keep left: data on 428 probands with left-sided CHD and their families”. Genetics in Medicine9 (2016): 914-923.‏
33. Zhao Wu., et al. "Mutations in VEGFA are associated with congenital left ventricular outflow tract obstruction”. Biochemical and Biophysical Research Communications2 (2010): 483-488.‏
34. Matsson Hans., et al. "Alpha-cardiac actin mutations produce atrial septal defects”. Human molecular genetics2 (2008): 256-265.‏
35. Durst Ronen., et al. "Mutations in DCHS1 cause mitral valve prolapse”. Nature7567 (2015): 109-113.‏
36. Micale Lucia., et al. "Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis”. European Journal of Human Genetics3 (2010): 317-323.‏
37. LaHaye Stephanie., et al. "Utilization of whole exome sequencing to identify causative mutations in familial congenital heart disease”. Circulation: Cardiovascular Genetics4 (2016): 320-329.‏
38. Kirk Edwin P., et al. "Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy”. The American Journal of Human Genetics2 (2007): 280-291.‏
39. Raissadati Alireza., et al. "Progress in late results among pediatric cardiac surgery patients: a population-based 6-decade study with 98% follow-up”. Circulation4 (2015): 347-353.‏
40. Pierpont Mary Ella., et al. "Genetic basis for congenital heart disease: revisited: a scientific statement from the American Heart Association”. Circulation21 (2018): e653-e711.‏
41. Page Donna J., et al. "Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of Fallot”. Circulation Research4 (2019): 553-563.‏
42. de Soysa T Yvanka., et al. "Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects”. Nature7767 (2019): 120-124.‏‏
43. Sizarov Aleksander., et al. "Formation of the building plan of the human heart: morphogenesis, growth, and differentiation”. Circulation10 (2011): 1125-1135.‏
44. Morton, Sarah U., et al. "Genomic frontiers in congenital heart disease”. Nature Reviews Cardiology1 (2022): 26-42.‏
45. Blue Gillian M., et al. "Advances in the genetics of congenital heart disease: a clinician’s guide”. Journal of the American College of Cardiology7 (2017): 859-870.‏
46. Cao Ce., et al. "Nkx2. 5: a crucial regulator of cardiac development, regeneration and diseases”. Frontiers in Cardiovascular Medicine10 (2023): 1270951.‏
47. Yamada Yuya., et al. "A novel NKX2-5 variant in a child with left ventricular noncompaction, atrial septal defect, atrioventricular conduction disorder, and syncope”. Journal of Clinical Medicine11 (2022): 3171.‏
48. Chen Jau-Nian and Mark C Fishman. "Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation”. Development12 (1996): 3809-3816.‏
49. Rosoff Marc L and Neil M Nathanson. "GATA factor-dependent regulation of cardiac m2 muscarinic acetylcholine gene transcription”. Journal of Biological Chemistry15 (1998): 9124-9129.‏
50. McDonald-McGinn Donna M., et al. "22q11. 2 deletion syndrome”. Nature Reviews Disease Primers1 (2015): 1-19.‏
51. Xu Huansheng., et al. "Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract”. (2004): 3217-3227.‏
52. Maurya Shailendra S., et al. "KDM6A knockout in human iPSCs alters the genome-wide histone methylation profile at active and poised enhancers, activating expression of ectoderm gene expression pathways”. bioRxiv (2021): 2021-2030.‏
53. Sen Rwik., et al. "The role of KMT2D and KDM6A in cardiac development: A cross-species analysis in humans, mice, and zebrafish”. bioRxiv2020 (2020): 2004.‏
54. Linglart Léa and Damien Bonnet. "Epigenetics and congenital heart diseases”. Journal of Cardiovascular Development and Disease6 (2022): 185.‏
55. Diab Nicholas S., et al. "Molecular genetics and complex inheritance of congenital heart disease”. Genes7 (2021): 1020.‏
56. Guo Tingwei., et al. "KDM6B interacts with TFDP1 to activate P53 signaling in regulating mouse palatogenesis”. Elife11 (2022): e74595.‏
57. Gažová Iveta., et al. "Lysine demethylases KDM6A and UTY: the X and Y of histone demethylation”. Molecular Genetics and Metabolism1 (2019): 31-44.‏
58. Gao Christine W., et al. "Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1”. PLoS Genetics6 (2024): e1011310.‏
59. Yi Zhujun., et al. "KDM6A regulates cell plasticity and pancreatic cancer progression by noncanonical activin pathway”. Cellular and Molecular Gastroenterology and Hepatology2 (2022): 643-667.‏

Citation

Citation: Majed Alsulami., et al. “Crucial Genes in Cardiogenesis: Their Role in Congenital Heart Disease”.Acta Scientific Medical Sciences 9.3 (2025): 112-118.

Copyright

Copyright: © 2025 Majed Alsulami., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.