Congenital heart disease (CHD) is one of the most common birth defects in humans, with an estimated incidence of about 0.8%, and is the leading cause of non-infectious death in infancy. The etiology of congenital heart disease is currently thought to contain: genetic factors, environmental factors, and the interaction of genetic and environmental factors; however, the exact cause of the disease remains unknown. Therefore, research on the etiology of precocious heart disease is of great importance to improve the quality of the birth population and to reduce the morbidity and mortality of the birth population. Since cardiac development is a complex event with multicellular and multigene involvement in regulation, any small disorder can lead to malformations in cardiac development. The genetic mechanism of precocious heart disease is well understood, and this paper provides a review of the reported genes related to precocious heart disease to better understand the genetic mechanism of precocious heart disease.
1. Human syndrome-related pathogenic genes of combined precocious heart disease
1.1 DiGeorge syndrome and TBX1 gene
DiGeorge syndrome is the most common chromosomal defect syndrome caused by a deletion of chromosome 22q11. The disease involves multiple organs, and cardiac malformations are mainly due to abnormal migration of the cardiac neural crest, including: aortic dissection, permanent arterial trunk (PTA), tetralogy of Fallot (TOF), right ventricular double outlet, and transposition of the great arteries. TBX1 knockout mice exhibit pharyngeal arch and cardiac malformations similar to DiGeorge syndrome, and TBX1 gene mutations. It was found that the TBX1 gene is expressed in the pharyngeal arch tissue of the endoderm and is involved in regulating the normal migration of cardiac neural crest cells, which are involved in the process of segregation of the main and pulmonary arteries, suggesting the relevance of the TBX1 gene to precordial disease.
1.2 Holt-Oram syndrome and TBX5 gene
Holt-Oram syndrome is mainly manifested by limb and heart malformations, so it is also known as heart-hand syndrome. Among these cardiac malformations are atrial septal defect (ASD), TOF and AV block. Haploinsufficient TBX5 gene causes Holt-Oram syndrome, and TBX5 mutation is the first single mutation found in a human heart septal defect malformation. This provides a clue for the discovery of target genes for this gene.
1.3 Char syndrome and the TFAP2β gene
Char syndrome also involves the hand and heart, and its characteristic cardiac malformation is patent ductus arteriosus (PDA) with mild hand deformity. β mutations block the major mutations that cause upper limb deformities, such as TBX5, and (2) the ductus arteriosus is more sensitive to changes in TFAP2β activity than the upper limb. Of course whether TFAP2β gene mutation causing PDA is also regulated by those transcription factors involved in ductal smooth muscle development needs to be studied in depth.
1.4 Noonan syndrome and PTPN11 gene
Noonan syndrome presents with a peculiar facial appearance, chest deformity and pulmonary stenosis (PS), and mutations in the PTPN11 gene encoding the protein phosphatase Shp2 cause Noonan syndrome with pulmonary artery stenosis [6]. Cardio-Facio-Cutaneous and Costello syndromes, which are clinically similar to Noonan syndrome, do not have PTPN11 gene mutations.Shp2 may be important in the RAS/MAPK pathway, which leads to enhanced RAS/MAPK (proto-oncogene – mitogen-activated protein kinase) signaling, while NF1 ( PTPN11 point mutant mice exhibit defects due to impaired movement of epithelial growth factor, which is an important link in the RAS/MAPK signaling pathway. Recently, mutations in MEK1/2 (mitogen-activated protein kinase), K-RAS and B-RAF (oncogene encoding serine/threonine kinase) have been identified in Cardio-Facio-Cutaneous syndrome, and mutations in H-RAS gene have been found in Costello syndrome. Recently, K-RAS mutations have also been identified in Noonan syndrome, suggesting that there may be some common genetic pathways in the genetic mechanisms of Noonan and Cardio-Facio-Cutaneous syndromes.
1.5 Alagille syndrome and NOTCH pathway
Alagille syndrome presents with liver disease, PS and/or with TOF. mutations in the JAG1 gene, the transmembrane ligand for the NOTCH family of receptors, are found in most Alagille syndromes, and similarly mutations in NOTCH2 can be found in Alagille syndromes without mutations in the JAG1 gene. Currently, NOTCH pathway abnormalities can be found in 75-95% of Alagille syndromes.
2. Causal genes associated with familial isolated precocious heart disease
Although studies of some human syndromes with combined prediabetes have helped to identify some causative genes for prediabetes, most prediabetes is isolated prediabetes without other tissue abnormalities, and studies of human prediabetes causative genes for which clear evidence has been found are as follows.
2.1 Genes associated with cardiac outflow tract malformations
The most common cardiac outflow tract malformation is a bilobed aortic valve with early calcification, which is thought to be associated with the chromosome 9q34-35 region and is found to have familial onset with premature discontinuation of the NOTCH1 gene codon. Early bileaflet aortic valve with calcification is often thought to be the result of hemodynamic disturbances caused by blood flow through the valvular fissure, but now valvular calcification is also found in familial patients without bileaflet aortic valve, suggesting that the primary gene defect involved in the NOTCH pathway may be associated with the development of certain degenerative diseases, and the mechanism may be that the NOTCH1 gene binds and represses osteogenic gene transcription through downstream target sites HRT1, 2 binding and repressing the activity of the osteogenic gene transcription factor Runx2 to regulate calcification.
2.2 Genes associated with cardiac septal defects
Mutations in the NKX2.5 gene in familial ASD and atrioventricular block (AVB) were the first identified examples of single gene mutations causing isolated precardiac disease, and similarly mutations in the NKX2.5 gene can be found in patients with disseminated precardiac disease. Mutations in the GATA-4 transcription factor gene have been identified in familial precocious heart disease with ASD, ventricular septal defect, or atrial septal defect without AVB. mutations in GATA-4 are manifested as codon-shifting mutations leading to premature codon aborts and missense mutations in Gly295Ser, which alter the binding of GATA-4 to NKX2.5 and TBX5. Since the target sites of GATA-4, NKX2.5 and TBX5 genes are cardiomyocytes, mutations in the heavy chain myosin (MHC6) gene have also been reported in patients with ASD.
3. Risk genes for disseminated precocious heart disease
The vast majority of precardiac diseases are disseminated rather than familial, and the occurrence of these precardiac diseases is thought to be the result of a combination of multiple genes. Mutations in some of the definitive precardiac pathogenic genes (NKX2.5, NOTCH1, JAG1, GATA4, MHC6 and TBX5), as described above, are found in no more than 5% of patients with precardiac disease in total. In the post-genomic phase, the study of risk genes for precocious heart disease has gradually intensified, and the following have been identified.
3.1 Enhancer of vascular endothelial growth factor
Knockout of amino acids at position 164 of vascular endothelial growth factor (VEGF) in mice creates a disease model of DiGeorge syndrome with cardiac manifestations of TOF; VEGF enhancers and three SNPs in the 5′ untranslated segment have been identified in certain patients with cardiac malformations identical to those of DiGeorge syndrome with concomitant precocious heart disease. current studies in Caucasians Enhancer haplointegration of VEGF was found to increase the incidence of disseminated TOF by 1.8-fold. enhancer haplointegration of VEGF decreases VEGF expression, but this also leads to a range of different diseases and not just precocious disease.
3.2 Methylene ethylene phosphate reductase
Methyl ethylene phosphate reductase (MTHFR) is required for cysteine and methionine metabolism in vivo, and pure mutations in MTHFR677C®T in 10% to 20% of Caucasian species can cause defects in neural tube development, which in turn are closely associated with precardiac disease. Therefore, progress has also been made in finding MTHFR677C®T mutations in large samples of disseminated precardiac disease.
In summary, gene defects or single gene mutations have now been identified as important etiologies in the study of precocious heart disease, but these genetic mutations with clear evidence are mostly found in genetic syndromes with precocious heart disease or familial precocious heart disease, and the causative genes of a large number of disseminated precocious heart diseases are still unclear or only confirmed in animal models. Therefore, with the maturation of DNA microarray technology, large-scale, high-throughput genetic screening for precocious heart disease may be a future research direction.