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Review

Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review

by
Alexandru Cristian Bolunduț
1,*,
Cecilia Lazea
1,2 and
Carmen Mihaela Mihu
3
1
1st Department of Pediatrics, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania
2
1st Pediatrics Clinic, Emergency Pediatric Hospital, 400370 Cluj-Napoca, Romania
3
Department of Histology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
*
Author to whom correspondence should be addressed.
Children 2023, 10(5), 812; https://doi.org/10.3390/children10050812
Submission received: 14 February 2023 / Revised: 23 April 2023 / Accepted: 27 April 2023 / Published: 29 April 2023
(This article belongs to the Section Pediatric Cardiology)
Review Reports Versions Notes

Abstract

:
Congenital heart defects (CHD) are the most common congenital abnormality, with an overall global birth prevalence of 9.41 per 1000 live births. The etiology of CHDs is complex and still poorly understood. Environmental factors account for about 10% of all cases, while the rest are likely explained by a genetic component that is still under intense research. Transcription factors and signaling molecules are promising candidates for studies regarding the genetic burden of CHDs. The present narrative review provides an overview of the current knowledge regarding some of the genetic mechanisms involved in the embryological development of the cardiovascular system. In addition, we reviewed the association between the genetic variation in transcription factors and signaling molecules involved in heart development, including TBX5, GATA4, NKX2-5 and CRELD1, and congenital heart defects, providing insight into the complex pathogenesis of this heterogeneous group of diseases. Further research is needed in order to uncover their downstream targets and the complex network of interactions with non-genetic risk factors for a better molecular–phenotype correlation.

1. Introduction

Congenital heart defects (CHD) can be defined as structural abnormalities of the heart and/or the great vessels present at birth and are caused by alterations in the normal embryological development of the cardiovascular system. They are a heterogeneous group of diseases. Botto et al. proposed a classification for etiologic studies based on anatomical, clinical and embryological similarity [1]. They divided CHDs into eight categories: conotruncal defects (including truncus arteriosus, the interrupted aortic arch, D-transposition of the great arteries, tetralogy of Fallot and the double outlet right ventricle), atrioventricular septal defect, anomalous-pulmonary venous return (total or partial), left ventricular outflow tract obstruction (including hypoplastic left heart syndrome, coarctation of aorta and aortic stenosis), right ventricular outflow tract obstruction (including pulmonary valve stenosis, tricuspid atresia, Ebstein malformation and pulmonary atresia), septal defects (ventricular or atrial), heterotaxy malformations, and complex defects (including the L-transposition of the great arteries, univentricular heart and other associations) [1].
CHDs are the most common congenital abnormality, followed by limb anomalies, congenital anomalies of the kidney and urinary tract and nervous system anomalies [2]. The overall global birth prevalence of CHDs reported was 9.41 per 1000 live births [3], which shows a substantial increase in recent decades [3,4]. The prevalence showed marked differences between different geographical areas [3,4]. The most common type is the ventricular septal defect (VSD), representing about 35% of all CHDs, followed by the atrial septal defect (ASD) and patent ductus arteriosus (PDA) [3]. The prevalence of ‘mild’ lesions (defects that usually have a less significant hemodynamic and clinical impact, including VSD, ASD and PDA) increased during the last decades, probably due to advances that led to more accurate detection, while the ‘severe’ lesions showed a relatively constant trend in prevalence [3].
The etiology of CHDs is complex and still poorly understood. Clearly identified environmental factors (non-genetic risk factors) account for about 10% of CHDs [5]. The most studied of them include maternal health conditions (such as obesity and diabetes mellitus), maternal alcohol consumption, maternal smoking, maternal exposure to certain drugs during pregnancy (antidepressants, anticonvulsants and antiarrhythmic drugs), maternal fever during the first trimester (which possibly correlates with the teratogenic effect of different microorganisms), paternal smoking and paternal advanced age [6,7]. Genetic contributions represent the remaining 90% [5]. Table 1 summarizes some of the current knowledge about the etiology of CHDs. In a review regarding their complex inheritance, Diab et al. concluded that more than half of CHDs do not have an identified etiology, which will probably, in time, be explained by gene-to-gene interactions, gene-to-environment interactions, polygenic inheritance or epigenetic mechanisms, all of which are still under intense research [5]. New studies based on single-cell RNA-sequencing and other functional genetics methods are starting to uncover the network of transcription factors and signaling molecules involved [8,9]. Whole-genome sequencing studies have underlined the implication of non-coding de novo mutations as part of the complex genetic model of CHDs, but their effect on the transcriptional activity of coding genes and their burden on the alteration of heart development is still unclear [10].
The aim of this narrative review is to provide an overview of the current knowledge regarding some of the genetic mechanisms involved in the embryological development of the cardiovascular system. We briefly summarized the embryologic stages of heart development and overviewed the role played by some transcription factors and signaling molecules in this process. We also reviewed their association with congenital heart defects, providing insight into the complex pathogenesis of this heterogeneous group of diseases.

2. Embryologic Stages of Heart Development

2.1. Formation of the Heart Tube

The heart is one of the first organs to develop in the human embryo. It originates mostly from the mesoderm, with the contribution of ectodermal-derived cells (neural crest cells) [11]. The heart-forming region (the first heart field) is composed by the first mesodermal cells that migrate through the primitive streak and position themselves in a horseshoe-like shape, rostral and lateral to the stomato-pharyngeal membrane [11,12,13]. During this process, they exit the region of blocked differentiation mediated by Wnt growth factors and enter an environment that promotes cardiomyocyte differentiation, via active Wnt inhibition; the expression of bone morphogenetic protein (BMP) growth factors; and other cardiac-specific transcription factors, such as Nkx2.5 and Islet1 [12,14,15,16].
The closure of the neural tube and the development of the nervous system determines the cranio-caudal and anterior folding of the embryo, which places the heart-forming region in its final position [11]. This process leads to the formation of the heart tube, a Y-shaped structure with two caudo-lateral inlet branches and one cranial outlet, which is initially attached to the body, anterior to the foregut, by the dorsal mesocardium [17] and organized in three layers: an outer layer of cardiomyocytes (termed primary myocardium), an inner layer of endocardial cells (a cell population that is also derived from the splanchnic mesoderm of the heart field at the same time as cardiomyocytes [11,18]) and an extracellular matrix between them (the cardiac jelly) [12]. After that, the heart tube starts to loop towards the right, in a progressive manner, forming a C-like and then an S-like structure [12,17]. The looping is mediated by the growth of the heart tube due to the addition of new cardiomyocytes, derived from the second heart field (located posteriorly from the first heart field), and migrated through the dorsal mesocardium [11,19,20].
The cellular ultrastructure of cardiomyocytes makes all of them capable of contraction (via sarcomeres), spontaneous depolarization and the conduction of the electrical impulses generated (via ion pumps or channels and gap junctions) [11,12]. Cardiomyocytes in various regions of the heart differ from one another by the intensity of these characteristics and are partly mediated by the expression of the T-Box (TBX) transcription factor family [11]. The fate of one cell is determined by its location in the developing heart via signals that promote the expression of certain transcription factors and other molecules [11].

2.2. Development of Heart Chambers

The looping of the heart tube represents a scaffold for the future four-chambered heart. During this process, the cardiac jelly between the endocardium and the myocardium disappears at the outer curvatures so the cardiomyocytes in these regions resume proliferation, along with differentiation, forming the primordia for the future ventricles at the arterial pole and the atrial appendices at the venous pole. This is referred to as the ballooning model [11]. The proliferating and differentiating cardiomyocytes are termed secondary or chamber myocardium and express specific genes such as the atrial natriuretic factor (Anf/Nppa) and Connexin 40 (Cx40/Gja5), a gap-junction protein [11,21]. The cardiomyocytes form endoluminal protrusions, called trabeculations, that grow via the addition of new cells at their base and assure the lengthening and thickening of the myocardium [12,20]. The initial ventricles have a trabecular phenotype. During heart maturation, under the influence of epicardial-derived fibroblasts, a compact layer develops, with a different set of markers expressed compared to the trabecular myocardium [22].
The secondary myocardium gives rise only to the trabeculated portion of the mature atria. The rest of the atrial myocardium forms via the incorporation of the venous system [11]. The systemic venous blood is retrieved to the heart by the left and right common cardinal veins. The pericardial cavity expands and incorporates the common cardinal veins, while cardiomyocytes encircle them, forming the so-called sinus venosus, with its right horn becoming the dorsal part of the right atrium [11,12]. The pulmonary venous system develops as a vascular plexus surrounding the embryonic foregut, which gives rise to the lung primordia. This plexus drains through a single vessel that is connected to the atrium in the midline via the dorsal mesocardium. Cardiomyocytes encircle the pulmonary vein and incorporate it into the future left atrium up to the second bifurcation, resulting in four pulmonary orifices [11,12].

2.3. Septation of the Heart

The septation of the heart is a complex process that leads to the development of its closed double circulation characteristic. The process starts with the formation of extracellular matrix cushions in the atrioventricular canal and the outflow tract, which are further populated by endocardium-derived mesenchymal cells [12].
Atrial septation begins with the primary septum, a crescent-shaped structure formed by the proliferation of atrial cells, growing towards the atrioventricular canal and closing the primary atrial foramen (ostium primum) by fusing with the major atrioventricular cushions [11,12]. To ensure the bypass of the pulmonary circulation characteristic for the fetal circulation, a secondary atrial foramen (ostium secundum) is formed in the primary septum by the apoptosis of the cells [23,24]. To complete the septation process, the muscular wall folds down to the right side of the primary septum, forming the secondary septum and completely covering the ostium secundum. The secondary septum is still incomplete, and the orifice that remains forms with the ostium secundum, an oblique canal termed the foramen ovale, which represents the right-to-left shunt characteristic to the fetal circulation [23,24]. At birth, due to the change in atrial blood pressure, the primary and secondary septum are pushed together and the atrial septation is completed [11,23].
The septation of the ventricles starts during the ballooning process with the formation of the muscular septum, by apposition, adding cells at its base from the adjacent growing left ventricular free wall [12]. With the inner curvature, the superior rim of the ventricular septum determines the ventricular foramen, which is functionally separated by the major (dorsal and ventral) atrioventricular cushions in a right and left portion [12]. The ventricular septation will become anatomically complete with the septation of the outflow tract.
The outflow tract connects the ventricles to the aortic sac, which in turn is connected to the third, fourth and fifth pairs of pharyngeal arch arteries [12]. The septation of the outflow tract starts at the level of the cushions from this region, in a spiral fashion and from distal to proximal, generating a 180° turn in the future aortic and pulmonary arteries [11,12]. The outflow tract cushions are populated with cells migrated from the secondary heart field, as well as cells migrated from the neural crests, which provide growth factors essential for the normal development of the region [12,25]. Proximally, the outflow tract septum will fuse with the atrioventricular cushions, forming the membranous ventricular septum, completing the anatomical septation of the ventricles. Distally, a protrusion of the pharyngeal mesenchyme, termed the aorto-pulmonary septum, connects with the outflow tract cushions, separating the emerging arteries [12]. The system of pharyngeal arch arteries will remodel and generate the adult arterial pattern at the end of the eighth week of development [12]. The cardiac jelly at the site of the atrioventricular and outflow tract cushions and ridges will remodel, forming the heart valves, in a complex process [11].
Table 2 summarizes the milestones of heart development and their connections with CHDs.

3. An Overview of Transcription Factors and Signaling Molecules Involved in the Development of CHD

3.1. TBX5

TBX5 is a transcription factor from the T-box family with a highly conserved expression pattern in the heart, forelimb and retina in different vertebrate species [26].

3.1.1. TBX5 in Heart Development

The T-box transcription factor family plays an important role in regulating the cardiomyocyte identity in the developing heart [11]. TBX5 demonstrates an expression gradient from the venous pole of the heart (the region of the developing atria) to the right ventricle and the outflow tract, where it is absent [11,26]. Recent studies on human embryonic stem cell-derived cardiomyocytes uncovered both structural and functional roles that can be attributed to TBX5 expression, which include upregulating sarcomere structure genes and genes involved in cellular calcium handling [27].
The transcription factor is involved in the septation of the heart, for both the atria and the ventricles. The location of the ventricular septum depends on the TBX5/TBX20 interaction, while the boundary between the TBX5 positive/TBX20 negative cardiomyocytes (specific to the left ventricle) and the TBX5 negative/TBX20 positive myocardium (specific to the right ventricle) appears to indicate the position of the interventricular septum [28,29]. In addition, the development of the atrial septum is dependent on the expression of TBX5 in the second heart field and is regulated by interactions with Sonic Hedgehog (SHH) signaling, with the SHH ligand secreted from the pulmonary endoderm [30,31].

3.1.2. TBX5 in the Development of the Ventricular Conduction System

TBX5 appears to play a central role in the development of the ventricular conduction system via the specification and regulation of gene expression. It activates the expression pattern for the fast-conducting phenotype characteristic for the ventricular conduction system cells by driving the gene regulatory network, composed of genes such as CX40, SCN5A, RYR2, KCNK3 or KCNJ2, and coding for Na+, K+ and Ca++ channels, both in the developing and the adult heart [26,32,33]. Van Ouwerkerk et al. proposed a murine model to evaluate the effects of a TBX5 missense mutation (c.373G>A; p.Gly125Arg) in relation to early onset atrial fibrillation. The mice showed variable RR intervals and a susceptibility to atrial fibrillation, similarly to patients with the similar mutation. The cardiomyocytes demonstrated decreased systolic and diastolic intracellular calcium concentrations, thus affecting action potentials, probably due to changes in the regulatory element activity and transcriptional regulation (epigenetic changes) induced by the TBX5 mutation, confirming the central role played by the transcription factor in the development of the conduction system [34].

3.1.3. Gene–Environment Interactions Involving TBX5

Zhang et al. demonstrated that increased maternal leucine levels in the first trimester of pregnancy increase the risk for congenital heart defects in the offspring due to the inhibition of TBX5 signaling. In an experimental model performed on mice, they showed that increasing the maternal leucine levels will increase embryonic lysine-leucylation, thus modifying the lysine residues in TBX5 and inhibiting its transcriptional activity [35]. This underlines the importance of gene–environment interactions and the complex mechanisms involved in the pathogenesis of CHD.

3.1.4. Genetic Variation Involving TBX5

TBX5 haploinsufficiency has been shown to be the cause of Holt–Oram syndrome (HOS), an autosomal dominant disorder affecting cardiac and upper limb development, with a high penetrance and variable expression [36,37,38]. The cardiac phenotype consists of congenital heart defects (mostly septal defects, the atrial septal defect being the most frequent) and conduction abnormalities, while the characteristic limb anomalies are bilateral and asymmetric radial ray defects [39]. The majority of the reported TBX5 mutations are nonsense or frameshift mutations, which result in the introduction of premature stop codons, obtaining a truncated protein with impaired function. Al-Qattan et al. reviewed the genotype–phenotype correlation in typical HOS patients resulting from missense mutations of TBX5, concluding that most of the mutations were found in the DNA-binding domain of the gene, thus affecting the interaction with other transcription factors regulating the embryological development of the heart and limbs (such as GATA4 or NKX2-5) and causing loss of function [40].
Recent reports have shown a heterogeneous pattern of genetic variants of the TBX5 gene in relation to heart disease, in addition to the known features of typical HOS, underlining the complex molecular regulation of the developing heart and uncovering new roles for this transcription factor during the embryological period. Table 3 summarizes some of the newly identified mutations involving TBX5 and their phenotype.

3.2. GATA4

GATA4 is a transcription factor from the GATA family characterized by a highly conserved two zinc fingers domain that binds to the specific DNA sequence 5′-(A/T)GATA(A/G)-3′ in the promoters of target genes [52].

3.2.1. GATA4 in Cardiomyocyte Differentiation

Many cardiac-specific genes possess GATA elements in their regulatory regions, including not only structural sarcomere genes, such as myosin light chain-3 (MYL3) or troponin C (TNNC1) and I (TNNI3), but also genes for Na+/Ca2+-exchanger (SLC8A3), acetylcholine receptor-M2 (CHRM2), cardiac-restricted ankyrine repeat protein (CARP), carnitine palmitoyltransferase-1b (CPT1B), and other transcription factors, such as NKX2-5, which have been shown to be regulated by GATA4 [52]. Due to the overlap in the DNA-binding region, the cardiac subfamily of GATA transcription factors (GATA4/5/6) exhibit redundant functions and interact with each other to ensure the specification of cardiac cells and subsequent heart development [53].
Zhao et al. suggested that GATA4 and GATA6 are essential for heart development by influencing the transcription factors network involved in the cardiomyocyte differentiation. They demonstrated that GATA4/GATA6 knockout mice presented with acardia, blocking the formation of the first heart field and the differentiation of the progenitor cells into cardiomyocytes, while the formation of the second heart field was independent of GATA4 activity [54]. Various in vitro studies have underlined the central role of the transcription factor and its interactions with other regulatory elements in inducing cardiac specification. For example, the combination of GATA4, NKX2-5 and TBX5 was sufficient for the activation of the cardiac genetic program, both for transdifferentiating mesodermal cells and for reprogramming postnatal fibroblast to differentiated cardiomyocytes [55,56].

3.2.2. GATA4 in the Development of the Atrioventricular Region

GATA4 has an important role in the development of the atrioventricular region, including the valvulo–septal complex. The endocardium and endocardial cushions have a high expression of the transcription factor, and it was shown that GATA4 mediates both epithelial-to-mesenchymal transition (EMT) in the endocardial cushions and the growth and remodeling of the atrioventricular cushions, playing an important role in valve development [57]. Furthermore, GATA4 interacts with different cofactors in order to promote cell-type-specific gene expression programs [53]. For example, Kim et al. demonstrated the interaction between GATA4 and RERE (arginine-glutamic acid dipeptide repeats gene), a cardiac-expressed nuclear receptor co-regulator, in the development of the membranous portion of the ventricular septum, via their effects on EMT and mesenchymal cell proliferation [58]. Functional analyses of both GATA4 and FOG2/ZFPM2 gene mutations have shown a disturbance in the normal interaction between the two transcription factors, leading to similar phenotypes (mainly conotruncal defects), suggesting that the gene pair has an important role in the development of the outflow tract [59,60]. In addition, GATA4 is involved in the localization of the atrioventricular canal by activating enhancers that lead to H3K27 acetylation, thus activating atrioventricular canal-specific gene loci. This is in contrast to its role in the chamber myocardium, where it determines deacetylation and gene repression [61,62]. In a murine model, GATA4 haploinsufficiency determined an impaired migration of Hedgehog-responsive progenitor cells from the second heart field in the outflow tract, causing CHDs [63]. Further studies have shown that GATA4, in association with NKX2-5, promotes the maturation of differentiated cardiomyocytes after the migration [64].

3.2.3. GATA4 in the Developed Heart and Genetic Variation Involving GATA4

The transcription factor plays an important role in the adult heart as well by promoting the compensatory mechanisms determined by different types of acquired cardiovascular diseases, such as hypertrophy and angiogenesis. GATA4 is upregulated by mechanical and neurohumoral stimuli, such as increased hemodynamic load, direct wall stretching, angiotensin II, and endothelin-1, thus activating hypertrophy-associated gene promoters [52,65].
Many GATA4 mutations are associated with congenital heart defects. Table 4 summarizes some of the identified mutations involving the genes and their phenotypes.

3.3. NKX2-5

The transcription factor NKX2-5 is part of the NK-2 homeodomain-containing family, which is related to the Drosophila tinman protein (essential for the development of the dorsal vessel in flies) and highly conserved in many different species, from flies to zebrafish and humans [74,75,76,77]. The family is characterized by a homeodomain that consists of a helix-turn-helix motif and binds to the specific DNA sequence 5′-T(C/T)AAGTG-3′ [74,75].

3.3.1. NKX2-5 in Heart Development

During the embryologic period, NKX2-5 is expressed in the mesodermal cells of the first heart field, as well as the second heart field and the endoderm underlying it, indicating a central role in the transcriptional regulation of the developing heart due to its expression in progenitor cells [75,76]. Tissue-specific deletions in mouse models have shown that the mesodermal expression of NKX2-5 is essential for heart development, with a heart phenotype similar to that of NKX2-5 knock-out mice in the mesodermal deletion group, while the endodermal expression has very little influence on the normal development of the heart [76].
George et al. revealed that NKX2-5 expression is essential for the maintenance of the ventricular identity of cells during cardiomyocyte differentiation and acts in a dose-dependent manner in preserving the chamber-specific molecular features during atrial and ventricular formation [78]. In addition, studies have shown that NKX2-5 plays a specific role in the development of the outflow tract and the right ventricle [76,77]. Immunohistochemistry studies have demonstrated an increased expression of NKX2-5 in the outflow tract wall, thus promoting the progressive maturation of the differentiated cardiomyocytes at this level [64].

3.3.2. NKX2-5 in the Development of the Ventricular Conduction System

NKX2-5 appears to be involved in the development of the conduction system by influencing the number of specific myocytes in a dose-dependent manner, with little effect on the transcriptional regulation of gap junction proteins [79]. Moreover, it directly activates the expression of several major cardiac ion-channels, such as SCN5A, CACNA1C and KCNH2, thus linking the gene with conduction disturbances [80]. Li et al. uncovered that NKX2-5 is required for maintaining the physiological function of the sinoatrial node, with sinus node dysfunction as a result of the downregulation of the transcription factor, although it is not essential for the morphological development of the structure [81].

3.3.3. Gene–Gene and Gene–Environment Interactions Involving NKX2-5

Various transcription factors and other regulatory elements interact with one another in order to mediate the normal development of the heart. For example, Vincentz et al. identified a direct interaction between NKX2-5 and MEF2C for ventricular chamber formation by influencing ventricular cardiomyocyte specification [82]. Cardiomyocyte differentiation promoted by NKX2-5 is regulated by BMP signaling via SMAD4, which controls not only the expression but also the nuclear localization of the transcription factor [83].
Environmental factors can determine a CHD, but, for the majority of them, the exact molecular mechanism is not yet fully understood. Lai et al. proposed a mechanism for the association between hyperhomocysteinemia and the development of heart malformations by the downregulation of NKX2-5 via its interactions with IGFBP5 [84]. Furthermore, Zhao et al. found a link between maternal gestational diabetes mellitus, single nucleotide polymorphisms of NKX2-5 and CHD [85].

3.3.4. Genetic Variation Involving NKX2-5

NKX2-5 is one of the most studied genes in relation to heart disease. It appears to be a hypermutable locus, with an estimation that from 2 to 4% of all CHDs can be explained by mutations in the transcription factor, with the majority of them involving the outflow tract and the septal region [75,86]. Table 5 summarizes some of the identified mutations involving genes and their phenotypes.

3.4. CRELD1

The Cysteine-Rich with EGF-Like Domains 1 (CRELD1) gene encodes for a protein that acts as a cell adhesion and signaling molecule, is highly conserved between species, ranging from C. elegans to Homo sapiens, and is expressed both during embryogenesis and adult life in a number of different tissues, but mainly the developing heart, limb buds, branchial arches and brain [94].

3.4.1. CRELD1 in Heart Development

During cardiac embryogenesis, CRELD1 is expressed in the cells of the atrioventricular canal, endocardial cushions and the outflow tract, being involved in the development of these structures [95]. Knock-out CRELD1 mice presented fewer cells and less extracellular matrices in the atrioventricular endocardial cushions than wild-type mice [96]. Studies have revealed an interaction between VEGF, which seems to act upstream of CRELD1, and the calcineurin/NFATc1 signaling pathway, with CRELD1 promoting the nuclear translocation of the transcription factor NFAT, is known to regulate genes involved in the development of the heart [95,96]. Using a murine model of the spatial inactivation of CRELD1, Beckert et al. uncovered that the gene plays an important role not only in the early stages of heart development but also in the maturation and the maintenance of the normal function of the myocardium by regulating transcriptional networks in both atria and ventricles that control the modeling of the extracellular matrix and trabecular formation [97].

3.4.2. Genetic Variation Involving CRELD1

CRELD1 mutations have been described in association with the development of atrioventricular septal defects (AVSD), in both isolated and syndromic patients, with an additional risk in Down syndrome patients, possibly due to the particular genetic background of trisomy 21 [98,99]. It was approximated that between 5 and 10% of the AVSD patients carry a missense mutation in this gene [96]. Table 6 summarizes the pathologic implications of CRELD1 mutations described so far.

3.5. Genetic Variations in Other Transcription Factor and Signaling Molecule Genes

The vascular endothelial growth factor (VEGF) family is essential for angiogenesis, and the pathway involving these signaling molecules is also a key regulator of heart morphogenesis [104]. VEGFA plays an important role in the early stages of heart development, influencing the formation of the heart tube, and its overexpression can lead to impaired heart tube elongation and looping [105]. In addition, it is involved in the development of the endocardial cushions by mediating the endothelial-to-mesenchymal transition; thus, alterations in the expression of VEGFA may lead to atrioventricular septal defects and dysplastic atrioventricular valves [106]. Single nucleotide polymorphisms of VEGFA, such as c.-2578C>A, c.+963C>T, c.-634C>G, c.-1154G>A and c.-460T>C, were associated with an increased risk of developing CHDs, especially for tetralogy of Fallot and ventricular septal defects [67,107,108,109]. Moreover, studies have shown that deficiencies in the VEGF signaling pathway, due to haploinsufficiency of VEGF receptors, also contribute to the pathogenesis of tetralogy of Fallot [110].
The bone morphogenetic protein (BMP) signaling pathway is involved in the differentiation of the cardiac mesoderm as it regulates the expression of NKX2-5 transcription factor [104]. Murine models have uncovered an important role played by BMP4 in the remodeling and expansion of the endocardial cushions; it is required for the normal septation of the outflow tract and the development of the semilunar valves [111]. This process is mediated by complex molecular interactions between BMP4 and TBX1 and by VEGFA [112,113]. Although studies have underlined its involvement in cardiac embryogenesis, the relationship between the genetic variation of BMP4 and CHDs in human populations is still being researched. The association between the single nucleotide polymorphism rs762642 and both atrial and ventricular septal defects was demonstrated in a Chinese population [114,115].
ISL1 is a transcription factor that characterizes the cardiac progenitor cells [116]. The genetic variants of the promoter of ISL1 (g.4581A>G, g.4630G>A, g.5085G>A) were associated with the development of tetralogy of Fallot by causing functional changes that alter the transcriptional activity of the promoter, downregulating the transcription factor and its downstream effectors [117]. Additionally, the promoter variants g.4335A>G, g.4477G>A and g.4613G>A were described in patients with ventricular septal defects, demonstrating a similar pathogenetic mechanism [116]. Furthermore, a loss-of-function mutation c.225C>G (p.Tyr75Ter) was identified in a patient presenting with double-outlet right ventricle, altering the transcriptional activity of the gene and the interactions with TBX20, another transcription factor involved in heart development [118].

4. Conclusions

As previously stated, CHDs are a heterogeneous group of disorders with complex underlying pathologic mechanisms. In one study, it was estimated that over 400 genes are likely to be involved in their etiology [119]. In addition to genetic mutations, the researchers’ focus was also directed towards common and non-coding variants, as well as epigenetic factors and interactions with environmental contributors, as an effort to uncover some of the missing heritability [104,119].
Understanding new concepts regarding heart development has led to a paradigm shift in the pathogenesis of CHDs, from the multifactorial inheritance hypothesis to the “one heart disease—several mechanisms—several genes” hypothesis. It states that having a heart disease may be caused by errors in several embryological mechanisms in a developmental sequence, each of which are orchestrated by a specific set of genes, similarly to the “off targets” model from cancer research [119,120]. This paradigm shift has practical implications by changing the focus from the anatomical defect to the developmental mechanism. In order to give adequate genetic advice, it is mandatory to describe the cardiac anatomy accurately so that the suggestive embryological pathways can be identified and candidate genes can be determined [120]. Providing a molecular diagnosis of CHDs is important not only for future family planning but also for effective future patient management, due to insights in the evolution of the disorders (for example, an association with conductance disturbances, cardiomyopathies or extracardiac symptoms), as well as the outcome after surgery or other treatments (some genetic variations have been described as risk factors for morbidity and mortality after surgery) [119].
Transcription factors and signaling molecules are promising candidates for studies regarding the genetic burden of CHD. Although many of the pathogenetic mechanisms surrounding heart development have been described, further research is needed in order to uncover their downstream targets and the complex network of interactions with non-genetic risk factors for a better molecular–phenotype correlation.

Author Contributions

Conceptualization, A.C.B., C.L. and C.M.M.; writing—original draft preparation, A.C.B.; writing—review and editing, C.L.; supervision, C.M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Botto, L.D.; Lin, A.E.; Riehle-Colarusso, T.; Malik, S.; Correa, A. Seeking Causes: Classifying and Evaluating Congenital Heart Defects in Etiologic Studies. Birth Defects Res. Part A-Clin. Mol. Teratol. 2007, 79, 714–727. [Google Scholar] [CrossRef] [PubMed]
  2. Dolk, H.; Loane, M.; Garne, E. The Prevalence of Congenital Anomalies in Europe. Adv. Exp. Med. Biol. 2010, 686, 349–364. [Google Scholar] [CrossRef] [PubMed]
  3. Liu, Y.; Chen, S.; Zühlke, L.; Black, G.C.; Choy, M.K.; Li, N.; Keavney, B.D. Global Birth Prevalence of Congenital Heart Defects 1970-2017: Updated Systematic Review and Meta-Analysis of 260 Studies. Int. J. Epidemiol. 2019, 48, 455–463. [Google Scholar] [CrossRef] [PubMed]
  4. Van Der Linde, D.; Konings, E.E.M.; Slager, M.A.; Witsenburg, M.; Helbing, W.A.; Takkenberg, J.J.M.; Roos-Hesselink, J.W. Birth Prevalence of Congenital Heart Disease Worldwide: A Systematic Review and Meta-Analysis. J. Am. Coll. Cardiol. 2011, 58, 2241–2247. [Google Scholar] [CrossRef] [PubMed]
  5. Diab, N.S.; Barish, S.; Dong, W.; Zhao, S.; Allington, G.; Yu, X.; Kahle, K.T.; Brueckner, M.; Jin, S.C. Molecular Genetics and Complex Inheritance of Congenital Heart Disease. Genes 2021, 12, 1020. [Google Scholar] [CrossRef] [PubMed]
  6. Zhang, T.N.; Wu, Q.J.; Liu, Y.S.; Lv, J.L.; Sun, H.; Chang, Q.; Liu, C.F.; Zhao, Y.H. Environmental Risk Factors and Congenital Heart Disease: An Umbrella Review of 165 Systematic Reviews and Meta-Analyses with More than 120 Million Participants. Front. Cardiovasc. Med. 2021, 8, 640729. [Google Scholar] [CrossRef] [PubMed]
  7. Kalisch-Smith, J.I.; Ved, N.; Sparrow, D.B. Environmental Risk Factors for Congenital Heart Disease. Cold Spring Harb. Perspect. Biol. 2020, 12, a037234. [Google Scholar] [CrossRef]
  8. Stone, N.R.; Gifford, C.A.; Thomas, R.; Pratt, K.J.B.; Samse-Knapp, K.; Mohamed, T.M.A.; Radzinsky, E.M.; Schricker, A.; Ye, L.; Yu, P.; et al. Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming. Cell Stem Cell 2019, 25, 87–102.e9. [Google Scholar] [CrossRef]
  9. Sahara, M.; Santoro, F.; Sohlmér, J.; Zhou, C.; Witman, N.; Leung, C.Y.; Mononen, M.; Bylund, K.; Gruber, P.; Chien, K.R. Population and Single-Cell Analysis of Human Cardiogenesis Reveals Unique LGR5 Ventricular Progenitors in Embryonic Outflow Tract. Dev. Cell 2019, 48, 475–490.e7. [Google Scholar] [CrossRef]
  10. Richter, F.; Morton, S.U.; Kim, S.W.; Kitaygorodsky, A.; Wasson, L.K.; Chen, K.M.; Zhou, J.; Qi, H.; Patel, N.; Depalma, S.R.; et al. Genomic Analyses Implicate Noncoding de Novo Variants in Congenital Heart Disease. Nat Genet. 2020, 52, 769–777. [Google Scholar] [CrossRef]
  11. Sylva, M.; Van den Hoff, M.J.B.; Moorman, A.F.M. Development of the Human Heart. Am. J. Med. Genet. Part A 2014, 164, 1347–1371. [Google Scholar] [CrossRef]
  12. Buijtendijk, M.F.J.; Barnett, P.; van den Hoff, M.J.B. Development of the Human Heart. Am. J. Med. Genet. Part C Semin. Med. Genet. 2020, 184, 7–22. [Google Scholar] [CrossRef] [PubMed]
  13. Moorman, A.F.M.; Christoffels, V.M.; Anderson, R.H.; Van Den Hoff, M.J.B. The Heart-Forming Fields: One or Multiple? Philos. Trans. R. Soc. B Biol. Sci. 2007, 362, 1257–1265. [Google Scholar] [CrossRef]
  14. Sizarov, A.; Ya, J.; De Boer, B.A.; Lamers, W.H.; Christoffels, V.M.; Moorman, A.F.M. Formation of the Building Plan of the Human Heart: Morphogenesis, Growth, and Differentiation. Circulation 2011, 123, 1125–1135. [Google Scholar] [CrossRef] [PubMed]
  15. Marvin, M.J.; Di Rocco, G.; Gardiner, A.; Bush, S.M.; Lassar, A.B. Inhibition of Wnt Activity Induces Heart Formation from Posterior Mesoderm. Genes Dev. 2001, 15, 316–327. [Google Scholar] [CrossRef] [PubMed]
  16. Harvey, R.P. Patterning the Vertebrate Heart. Nat. Rev. Genet. 2002, 3, 544–556. [Google Scholar] [CrossRef] [PubMed]
  17. Le Garrec, J.F.; Domínguez, J.N.; Desgrange, A.; Ivanovitch, K.D.; Raphaël, E.; Bangham, J.A.; Torres, M.; Coen, E.; Mohun, T.J.; Meilhac, S.M. A Predictive Model of Asymmetric Morphogenesis from 3D Reconstructions of Mouse Heart Looping Dynamics. Elife 2017, 6, e28951. [Google Scholar] [CrossRef]
  18. Cohen-Gould, L.; Mikawa, T. The Fate Diversity of Mesodermal Cells within the Heart Field during Chicken Early Embryogenesis. Dev. Biol. 1996, 177, 265–273. [Google Scholar] [CrossRef]
  19. Bayraktar, M.; Männer, J. Cardiac Looping May Be Driven by Compressive Loads Resulting from Unequal Growth of the Heart and Pericardial Cavity. Observations on a Physical Simulation Model. Front. Physiol. 2014, 5, 430. [Google Scholar] [CrossRef]
  20. De Boer, B.A.; van den Berg, G.; de Boer, P.A.J.; Moorman, A.F.M.; Ruijter, J.M. Growth of the Developing Mouse Heart: An Interactive Qualitative and Quantitative 3D Atlas. Dev. Biol. 2012, 368, 203–213. [Google Scholar] [CrossRef]
  21. Houweling, A.C.; Somi, S.; Van Den Hoff, M.J.B.; Moorman, A.F.M.; Christoffels, V.M. Developmental Pattern of ANF Gene Expression Reveals a Strict Localization of Cardiac Chamber Formation in Chicken. Anat. Rec. 2002, 266, 93–102. [Google Scholar] [CrossRef] [PubMed]
  22. Ieda, M.; Tsuchihashi, T.; Ivey, K.N.; Ross, R.S.; Hong, T.T.; Shaw, R.M.; Srivastava, D. Cardiac Fibroblasts Regulate Myocardial Proliferation through Β1 Integrin Signaling. Dev. Cell 2009, 16, 233–244. [Google Scholar] [CrossRef]
  23. Jensen, B.; Wang, T.; Moorman, A.F.M. Evolution and Development of the Atrial Septum. Anat. Rec. 2019, 302, 32–48. [Google Scholar] [CrossRef] [PubMed]
  24. Naqvi, N.; McCarthy, K.P.; Ho, S.Y. Anatomy of the Atrial Septum and Interatrial Communications. J. Thorac. Dis. 2018, 10, S2837–S2847. [Google Scholar] [CrossRef] [PubMed]
  25. Keyte, A.L.; Alonzo-johnsen, M.; Hutson, M.R. Evolutionary and Developmental Origins of the Cardiac Neural Crest: Building a Divided Outflow Tract. Birth Defects Res. C Embryo Today 2014, 102, 309–323. [Google Scholar] [CrossRef]
  26. Steimle, J.D.; Moskowitz, I.P. TBX5: A Key Regulator of Heart Development, 1st ed.; Elsevier Inc.: Amsterdam, The Netherlands, 2017; Volume 122. [Google Scholar]
  27. Pezhouman, A.; Nguyen, N.B.; Sercel, A.J.; Nguyen, T.L.; Daraei, A.; Sabri, S.; Chapski, D.J.; Zheng, M.; Patananan, A.N.; Ernst, J.; et al. Transcriptional, Electrophysiological, and Metabolic Characterizations of HESC-Derived First and Second Heart Fields Demonstrate a Potential Role of TBX5 in Cardiomyocyte Maturation. Front. Cell Dev. Biol. 2021, 9, 3560. [Google Scholar] [CrossRef]
  28. Takeuchi, J.K.; Ohgi, M.; Koshiba-Takeuchi, K.; Shiratori, H.; Sakaki, I.; Ogura, K.; Saijoh, Y.; Ogura, T. Tbx5 Specifies the Left/Right Ventricles and Ventricular Septum Position during Cardiogenesis. Development 2003, 130, 5953–5964. [Google Scholar] [CrossRef]
  29. Koshiba-Takeuchi, K.; Mori, A.D.; Kaynak, B.L.; Cebra-Thomas, J.; Sukonnik, T.; Georges, R.O.; Latham, S.; Beck, L.; Henkelman, R.M.; Black, B.L.; et al. Reptilian Heart Development and the Molecular Basis of Cardiac Chamber Evolution. Nature 2009, 461, 95–98. [Google Scholar] [CrossRef]
  30. Hoffmann, A.D.; Peterson, M.A.; Friedland-Little, J.M.; Anderson, S.A.; Moskowitz, I.P. Sonic Hedgehog Is Required in Pulmonary Endoderm for Atrial Septation. Development 2009, 136, 1761–1770. [Google Scholar] [CrossRef]
  31. Xie, L.; Hoffmann, A.D.; Burnicka-Turek, O.; Friedland-Little, J.M.; Zhang, K.; Moskowitz, I.P. Tbx5-Hedgehog Molecular Networks Are Essential in the Second Heart Field for Atrial Septation. Dev. Cell 2012, 23, 280–291. [Google Scholar] [CrossRef]
  32. Burnicka-Turek, O.; Broman, M.T.; Steimle, J.D.; Boukens, B.J.; Petrenko, N.B.; Ikegami, K.; Nadadur, R.D.; Qiao, Y.; Arnolds, D.E.; Yang, X.H.; et al. Transcriptional Patterning of the Ventricular Cardiac Conduction System. Circ. Res. 2020, 127, E94–E106. [Google Scholar] [CrossRef] [PubMed]
  33. Moskowitz, I.P.G.; Pizard, A.; Patel, V.V.; Bruneau, B.G.; Kim, J.B.; Kupershmidt, S.; Roden, D.; Berul, C.I.; Seidman, C.E.; Seidman, J.G. The T-Box Transcription Factor Tbx5 Is Required for the Patterning and Maturation of the Murine Cardiac Conduction System. Development 2004, 131, 4107–4116. [Google Scholar] [CrossRef] [PubMed]
  34. Van Ouwerkerk, A.F.; Bosada, F.M.; Van Duijvenboden, K.; Houweling, A.C.; Scholman, K.T.; Wakker, V.; Allaart, C.P.; Uhm, J.S.; Mathijssen, I.B.; Baartscheer, T.; et al. Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction. Circulation 2022, 145, 606–619. [Google Scholar] [CrossRef]
  35. Zhang, X.; Liu, L.; Chen, W.C.; Wang, F.; Cheng, Y.R.; Liu, Y.M.; Lai, Y.F.; Zhang, R.J.; Qiao, Y.N.; Yuan, Y.Y.; et al. Gestational Leucylation Suppresses Embryonic T-Box Transcription Factor 5 Signal and Causes Congenital Heart Disease. Adv. Sci. 2022, 9, 2201034. [Google Scholar] [CrossRef]
  36. Holt, M.; Oram, S. Familial Heart Disease with Skeletal Malformations. Br. Heart J. 1960, 22, 236–242. [Google Scholar] [CrossRef] [PubMed]
  37. Basson, C.T.; Bachinsky, D.R.; Lin, R.C.; Levi, T.; Elkins, J.A.; Soults, J.; Grayzel, D.; Kroumpouzou, E.; Traill, T.A.; Leblanc-Straceski, J.; et al. Mutations in Human TBX5 [Corrected] Cause Limb and Cardiac Malformation in Holt-Oram Syndrome. Nat. Genet. 1997, 15, 30–35. [Google Scholar] [CrossRef]
  38. Li, Q.Y.; Newbury-Ecob, R.A.; Terrett, J.A.; Wilson, D.I.; Curtis, A.R.; Yi, C.H.; Gebuhr, T.; Bullen, P.J.; Robson, S.C.; Strachan, T.; et al. Holt-Oram Syndrome Is Caused by Mutations in TBX5, a Member of the Brachyury (T) Gene Family. Nat. Genet. 1997, 15, 21–29. [Google Scholar] [CrossRef]
  39. Vanlerberghe, C.; Jourdain, A.S.; Ghoumid, J.; Frenois, F.; Mezel, A.; Vaksmann, G.; Lenne, B.; Delobel, B.; Porchet, N.; Cormier-Daire, V.; et al. Holt-Oram Syndrome: Clinical and Molecular Description of 78 Patients with TBX5 Variants. Eur. J. Hum. Genet. 2019, 27, 360–368. [Google Scholar] [CrossRef]
  40. Al-Qattan, M.M.; Abou Al-Shaar, H. Molecular Basis of the Clinical Features of Holt-Oram Syndrome Resulting from Missense and Extended Protein Mutations of the TBX5 Gene as Well as TBX5 Intragenic Duplications. Gene 2015, 560, 129–136. [Google Scholar] [CrossRef]
  41. Azab, B.; Aburizeg, D.; Ji, W.; Jeffries, L.; Isbeih, N.J.; Al-Akily, A.S.; Mohammad, H.; Osba, Y.A.; Shahin, M.A.; Dardas, Z.; et al. TBX5 Variant with the Novel Phenotype of Mixed-Type Total Anomalous Pulmonary Venous Return in Holt-Oram Syndrome and Variable Intrafamilial Heart Defects. Mol. Med. Rep. 2022, 25, 1–13. [Google Scholar] [CrossRef]
  42. Yoshida, A.; Morisaki, H.; Nakaji, M.; Kitano, M.; Kim, K.S.; Sagawa, K.; Ishikawa, S.; Satokata, I.; Mitani, Y.; Kato, H.; et al. Genetic Mutation Analysis in Japanese Patients with Non-Syndromic Congenital Heart Disease. J. Hum. Genet. 2016, 61, 157–162. [Google Scholar] [CrossRef]
  43. Miyao, N.; Hirono, K.; Hata, Y.; Yoshimura, N.; Ichida, F. Novel Compound Heterozygous TBX5 Variants May Induce Hypoplastic Left Heart Syndrome. Pediatr. Int. 2019, 61, 607–609. [Google Scholar] [CrossRef] [PubMed]
  44. Postma, A.V.; Van De Meerakker, J.B.A.; Mathijssen, I.B.; Barnett, P.; Christoffels, V.M.; Ilgun, A.; Lam, J.; Wilde, A.A.M.; Deprez, R.H.L.; Moorman, A.F.M. A Gain-of-Function TBX5 Mutation Is Associated with Atypical Holt-Oram Syndrome and Paroxysmal Atrial Fibrillation. Circ. Res. 2008, 102, 1433–1442. [Google Scholar] [CrossRef]
  45. Markunas, A.M.; Manivannan, P.K.R.; Ezekian, J.E.; Agarwal, A.; Eisner, W.; Alsina, K.; Allen, H.D.; Wray, G.A.; Kim, J.J.; Wehrens, X.H.T.; et al. TBX5-Encoded T-Box Transcription Factor 5 Variant T223M Is Associated with Long QT Syndrome and Pediatric Sudden Cardiac Death. Am. J. Med. Genet. Part A 2021, 185, 923–929. [Google Scholar] [CrossRef]
  46. Patterson, J.; Coats, C.; McGowan, R. Familial Dilated Cardiomyopathy Associated with Pathogenic TBX5 Variants: Expanding the Cardiac Phenotype Associated with Holt–Oram Syndrome. Am. J. Med. Genet. Part A 2020, 182, 1725–1734. [Google Scholar] [CrossRef]
  47. Morine, M.; Kohmoto, T.; Masuda, K.; Inagaki, H.; Watanabe, M.; Naruto, T.; Kurahashi, H.; Maeda, K.; Imoto, I. A Unique TBX5 Microdeletion with Microinsertion Detected in Patient with Holt-Oram Syndrome. Am. J. Med. Genet. Part A 2015, 167, 3192–3196. [Google Scholar] [CrossRef]
  48. Kimura, M.; Kikuchi, A.; Ichinoi, N.; Kure, S. Novel TBX5 Duplication in a Japanese Family with Holt–Oram Syndrome. Pediatr. Cardiol. 2015, 36, 244–247. [Google Scholar] [CrossRef]
  49. Patel, C.; Silcock, L.; McMullan, D.; Brueton, L.; Cox, H. TBX5 Intragenic Duplication: A Family with an Atypical Holt-Oram Syndrome Phenotype. Eur. J. Hum. Genet. 2012, 20, 863–869. [Google Scholar] [CrossRef] [PubMed]
  50. Bogarapu, S.; Bleyl, S.B.; Calhoun, A.; Viskochil, D.; Saarel, E.V.; Everitt, M.D.; Frank, D.U. Phenotype of a Patient with Contiguous Deletion of TBX5 and TBX3: Expanding the Disease Spectrum. Am. J. Med. Genet. Part A 2014, 164, 1304–1309. [Google Scholar] [CrossRef] [PubMed]
  51. Cenni, C.; Andres, S.; Hempel, M.; Strom, T.M.; Thomas, E.; Davies, A.; Timoney, N.; Frigiola, A.; Logan, M.; Holder-Espinasse, M. TBX3 and TBX5 Duplication: A Family with an Atypical Overlapping Holt-Oram/Ulnar-Mammary Syndrome Phenotype. Eur. J. Med. Genet. 2021, 64, 104213. [Google Scholar] [CrossRef]
  52. Pikkarainen, S.; Tokola, H.; Kerkelä, R.; Ruskoaho, H. GATA Transcription Factors in the Developing and Adult Heart. Cardiovasc. Res. 2004, 63, 196–207. [Google Scholar] [CrossRef]
  53. Afouda, B.A. Towards Understanding the Gene-Specific Roles of GATA Factors in Heart Development: Does GATA4 Lead the Way? Int. J. Mol. Sci. 2022, 23, 5255. [Google Scholar] [CrossRef]
  54. Zhao, R.; Watt, A.J.; Battle, M.A.; Li, J.; Bondow, B.J.; Duncan, S.A. Loss of Both GATA4 and GATA6 Blocks Cardiac Myocyte Differentiation and Results in Acardia in Mice. Dev. Biol. 2008, 317, 614–619. [Google Scholar] [CrossRef]
  55. Ieda, M.; Fu, J.D.; Delgado-Olguin, P.; Vedantham, V.; Hayashi, Y.; Bruneau, B.G.; Srivastava, D. Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell 2010, 142, 375–386. [Google Scholar] [CrossRef]
  56. Takeuchi, J.K.; Bruneau, B.G. Directed Transdifferentiation of Mouse Mesoderm to Heart Tissue by Defined Factors. Nature 2009, 459, 708–711. [Google Scholar] [CrossRef]
  57. Rivera-Feliciano, J.; Lee, K.H.; Kong, S.W.; Rajagopal, S.; Ma, Q.; Springer, Z.; Izumo, S.; Tabin, C.J.; Pu, W.T. Development of Heart Valves Requires Gata4 Expression in Endothelial-Derived Cells. Development 2006, 133, 3607–3618. [Google Scholar] [CrossRef]
  58. Kim, B.J.; Zaveri, H.P.; Jordan, V.K.; Hernandez-Garcia, A.; Jacob, D.J.; Zamora, D.L.; Yu, W.; Schwartz, R.J.; Scott, D.A. RERE Deficiency Leads to Decreased Expression of GATA4 and the Development of Ventricular Septal Defects. DMM Dis. Model. Mech. 2018, 11, dmm031534. [Google Scholar] [CrossRef] [PubMed]
  59. Pu, T.; Liu, Y.; Xu, R.; Li, F.; Chen, S.; Sun, K. Identification of ZFPM2 Mutations in Sporadic Conotruncal Heart Defect Patients. Mol. Genet. Genomics 2018, 293, 217–223. [Google Scholar] [CrossRef] [PubMed]
  60. Zhao, Z.; Zhan, Y.; Chen, W.; Ma, X.; Sheng, W.; Huang, G. Functional Analysis of Rare Variants of GATA4 Identified in Chinese Patients with Congenital Heart Defect. Genesis 2019, 57, e23333. [Google Scholar] [CrossRef] [PubMed]
  61. Stefanovic, S.; Barnett, P.; Van Duijvenboden, K.; Weber, D.; Gessler, M.; Christoffels, V.M. GATA-Dependent Regulatory Switches Establish Atrioventricular Canal Specificity during Heart Development. Nat. Commun. 2014, 5, 3680. [Google Scholar] [CrossRef]
  62. He, A.; Gu, F.; Hu, Y.; Ma, Q.; Yi Ye, L.; Akiyama, J.A.; Visel, A.; Pennacchio, L.A.; Pu, W.T. Dynamic GATA4 Enhancers Shape the Chromatin Landscape Central to Heart Development and Disease. Nat. Commun. 2014, 5, 10966. [Google Scholar] [CrossRef]
  63. Liu, J.; Cheng, H.; Xiang, M.; Zhou, L.; Wu, B.; Moskowitz, I.P.; Zhang, K.; Xie, L. Gata4 Regulates Hedgehog Signaling and Gata6 Expression for Outflow Tract Development. PLoS Genet. 2019, 15, e1007711. [Google Scholar] [CrossRef] [PubMed]
  64. Yang, Y.P.; Li, H.R.; Cao, X.M.; Wang, Q.X.; Qiao, C.J.; Ya, J. Second Heart Field and the Development of the Outflow Tract in Human Embryonic Heart. Dev. Growth Differ. 2013, 55, 359–367. [Google Scholar] [CrossRef] [PubMed]
  65. Whitcomb, J.; Gharibeh, L.; Nemer, M. From Embryogenesis to Adulthood: Critical Role for GATA Factors in Heart Development and Function. IUBMB Life 2020, 72, 53–67. [Google Scholar] [CrossRef]
  66. Shichiri, Y.; Kato, Y.; Inagaki, H.; Kato, T.; Ishihara, N.; Miyata, M.; Boda, H.; Kojima, A.; Miyake, M.; Kurahashi, H. A Case of 46,XY Disorders of Sex Development with Congenital Heart Disease Caused by a GATA4 Variant. Congenit. Anom. 2022, 62, 203–207. [Google Scholar] [CrossRef] [PubMed]
  67. Sarwar, S.; Ehsan, F.; Shabana; Tahir, A.; Jamil, M.; Shahid, S.U.; Khan, A.; Hasnain, S. First Report of Polymorphisms in MTRR, GATA4, VEGF, and ISL1 Genes in Pakistani Children with Isolated Ventricular Septal Defects (VSD). Ital. J. Pediatr. 2021, 47, 4–9. [Google Scholar] [CrossRef] [PubMed]
  68. Bu, H.; Sun, G.; Zhu, Y.; Yang, Y.; Tan, Z.; Zhao, T.; Hu, S. The M310T Mutation in the GATA4 Gene Is a Novel Pathogenic Target of the Familial Atrial Septal Defect. BMC Cardiovasc. Disord. 2021, 21, 12. [Google Scholar] [CrossRef]
  69. Behiry, E.G.; Al-Azzouny, M.A.; Sabry, D.; Behairy, O.G.; Salem, N.E. Association of NKX2-5, GATA4, and TBX5 Polymorphisms with Congenital Heart Disease in Egyptian Children. Mol. Genet. Genomic Med. 2019, 7, e612. [Google Scholar] [CrossRef]
  70. Alonso-Montes, C.; Martín, M.; Martínez-Arias, L.; Coto, E.; Naves-Díaz, M.; Morís, C.; Cannata-Andía, J.B.; Rodríguez, I. Variants in Cardiac GATA Genes Associated with Bicuspid Aortic Valve. Eur. J. Clin. Investig. 2018, 48, e13027. [Google Scholar] [CrossRef] [PubMed]
  71. Fan, D.; Pang, S.; Chen, J.; Shan, J.; Cheng, Q.; Yan, B. Identification and Functional Study of GATA4 Gene Regulatory Variants in Atrial Septal Defects. BMC Cardiovasc. Disord. 2021, 21, 321. [Google Scholar] [CrossRef]
  72. Floriani, M.A.; Glaeser, A.B.; Dorfman, L.E.; Agnes, G.; Rosa, R.F.M.; Zen, P.R.G. GATA4 Deletions Associated with Congenital Heart Diseases in South Brazil. J. Pediatr. Genet. 2021, 10, 092–097. [Google Scholar] [CrossRef]
  73. Wat, M.J.; Shchelochkov, O.A.; Holder, A.M.; Breman, A.M.; Dagli, A.; Bacino, C.; Scaglia, F.; Zori, R.T.; Cheung, S.W.; Scott, D.A.; et al. Chromosome 8p23.1 Deletions as a Cause of Complex Congenital Heart Defects and Diaphragmatic Hernia. Am. J. Med. Genet. Part A 2009, 149, 1661–1677. [Google Scholar] [CrossRef]
  74. Bartlett, H.; Veenstra, G.J.C.; Weeks, D.L. Examining the Cardiac NK-2 Genes in Early Heart Development. Pediatr. Cardiol. 2010, 31, 335–341. [Google Scholar] [CrossRef]
  75. Reamon-Buettner, S.M.; Borlak, J. NKX2-5: An Update on This Hypermutable Homeodomain Protein and Its Role in Human Congenital Heart Disease (CHD). Hum. Mutat. 2010, 31, 1185–1194. [Google Scholar] [CrossRef] [PubMed]
  76. Zhang, L.; Nomura-Kitabayashi, A.; Sultana, N.; Cai, W.; Cai, X.; Moon, A.M.; Cai, C.L. Mesodermal Nkx2.5 Is Necessary and Sufficient for Early Second Heart Field Development. Dev. Biol. 2014, 390, 68–79. [Google Scholar] [CrossRef] [PubMed]
  77. Clark, C.D.; Zhang, B.; Lee, B.; Evans, S.I.; Lassar, A.B.; Lee, K.H. Evolutionary Conservation of Nkx2.5 Autoregulation in the Second Heart Field. Dev. Biol. 2013, 374, 198–209. [Google Scholar] [CrossRef]
  78. George, V.; Colombo, S.; Targoff, K.L. An Early Requirement for Nkx2.5 Ensures the First and Second Heart Field Ventricular Identity and Cardiac Function into Adulthood. Dev. Biol. 2015, 400, 10–22. [Google Scholar] [CrossRef] [PubMed]
  79. Jay, P.Y.; Harris, B.S.; Maguire, C.T.; Buerger, A.; Wakimoto, H.; Tanaka, M.; Kupershmidt, S.; Roden, D.M.; Schultheiss, T.M.; O’Brien, T.X.; et al. Nkx2-5 Mutation Causes Anatomic Hypoplasia of the Cardiac Conduction System. J. Clin. Investig. 2004, 113, 1130–1137. [Google Scholar] [CrossRef]
  80. Furtado, M.B.; Wilmanns, J.C.; Chandran, A.; Tonta, M.; Biben, C.; Eichenlaub, M.; Coleman, H.A.; Berger, S.; Bouveret, R.; Singh, R.; et al. A Novel Conditional Mouse Model for NKX2-5 Reveals Transcriptional Regulation of Cardiac Ion Channels. Differentiation 2015, 91, 29–41. [Google Scholar] [CrossRef] [PubMed]
  81. Li, H.; Li, D.; Wang, Y.; Huang, Z.; Xu, J.; Yang, T.; Wang, L.; Tang, Q.; Cai, C.L.; Huang, H.; et al. Nkx2-5 Defines a Subpopulation of Pacemaker Cells and Is Essential for the Physiological Function of the Sinoatrial Node in Mice. Development 2019, 146, dev178145. [Google Scholar] [CrossRef]
  82. Vincentz, J.W.; Barnes, R.M.; Firulli, B.A.; Conway, S.J.; Firulli, A.B. Cooperative Interaction of Nkx2.5 and Mef2c Transcription Factors during Heart Development. Dev. Dyn. 2008, 237, 3809–3819. [Google Scholar] [CrossRef]
  83. Hu, W.; Dong, A.; Karasaki, K.; Sogabe, S.; Okamoto, D.; Saigo, M.; Ishida, M.; Yoshizumi, M.; Kokubo, H. Smad4 Regulates the Nuclear Translocation of Nkx2-5 in Cardiac Differentiation. Sci. Rep. 2021, 11, 1–10. [Google Scholar] [CrossRef]
  84. Lai, G.; Wang, L.; Li, Z.; Zhao, Y. Homocysteine Downregulates Cardiac Homeobox Transcription Factor NKX2.5 via IGFBP5. Am. J. Physiol.-Hear. Circ. Physiol. 2020, 319, H1380–H1386. [Google Scholar] [CrossRef] [PubMed]
  85. Zhao, M.; Diao, J.; Huang, P.; Li, J.; Li, Y.; Yang, Y.; Luo, L.; Zhang, S.; Chen, L.; Wang, T.; et al. Association of Maternal Diabetes Mellitus and Polymorphisms of the NKX2.5 Gene in Children with Congenital Heart Disease: A Single Centre-Based Case-Control Study. J. Diabetes Res. 2020, 2020, 3854630. [Google Scholar] [CrossRef]
  86. Benson, D.W. Genetic Origins of Pediatric Heart Disease. Pediatr. Cardiol. 2010, 31, 422–429. [Google Scholar] [CrossRef] [PubMed]
  87. Dixit, R.; Narasimhan, C.; Balekundri, V.I.; Agrawal, D.; Kumar, A.; Mohapatra, B. Functional Analysis of Novel Genetic Variants of NKX2-5 Associated with Nonsyndromic Congenital Heart Disease. Am. J. Med. Genet. Part A 2021, 185, 3644–3663. [Google Scholar] [CrossRef]
  88. Rozqie, R.; Satwiko, M.G.; Anggrahini, D.W.; Sadewa, A.H.; Gunadi; Hartopo, A.B.; Mumpuni, H.; Dinarti, L.K. NKX2-5 Variants Screening in Patients with Atrial Septal Defect in Indonesia. BMC Med. Genom. 2022, 15, 37. [Google Scholar] [CrossRef] [PubMed]
  89. Reamon-Buettner, S.M.; Sattlegger, E.; Ciribilli, Y.; Inga, A.; Wessel, A.; Borlak, J. Transcriptional Defect of an Inherited NKX2-5 Haplotype Comprising a SNP, a Nonsynonymous and a Synonymous Mutation, Associated with Human Congenital Heart Disease. PLoS ONE 2013, 8, e83295. [Google Scholar] [CrossRef]
  90. Nazeer, N.U.; Bhat, M.A.; Rah, B.; Bhat, G.R.; Wani, S.I.; Yousuf, A.; Dar, A.M.; Afroze, D. Mutational Assessment in NKX2-5 and ACTC1 Genes in Patients with Congenital Cardiac Septal Defect (CCSD) from Ethnic Kashmiri Population. Int. J. Environ. Res. Public Health 2022, 19, 9884. [Google Scholar] [CrossRef]
  91. Xu, Y.J.; Qiu, X.B.; Yuan, F.; Shi, H.Y.; Xu, L.; Hou, X.M.; Qu, X.K.; Liu, X.; Huang, R.T.; Xue, S.; et al. Prevalence and Spectrum of NKX2.5 Mutations in Patients with Congenital Atrial Septal Defect and Atrioventricular Block. Mol. Med. Rep. 2017, 15, 2247–2254. [Google Scholar] [CrossRef]
  92. Qu, X.K.; Qiu, X.B.; Yuan, F.; Wang, J.; Zhao, C.M.; Liu, X.Y.; Zhang, X.L.; Li, R.G.; Xu, Y.J.; Hou, X.M.; et al. A Novel NKX2.5 Loss-of-Function Mutation Associated with Congenital Bicuspid Aortic Valve. Am. J. Cardiol. 2014, 114, 1891–1895. [Google Scholar] [CrossRef]
  93. Izumi, K.; Noon, S.; Wilkens, A.; Krantz, I.D. NKX2.5 Mutation Identification on Exome Sequencing in a Patient with Heterotaxy. Eur. J. Med. Genet. 2014, 57, 558–561. [Google Scholar] [CrossRef]
  94. Rupp, P.A.; Fouad, G.T.; Egelston, C.A.; Reifsteck, C.A.; Olson, S.B.; Knosp, W.M.; Glanville, R.W.; Thornburg, K.L.; Robinson, S.W.; Maslen, C.L. Identification, Genomic Organization and MRNA Expression of CRELD1, the Founding Member of a Unique Family of Matricellular Proteins. Gene 2002, 293, 47–57. [Google Scholar] [CrossRef]
  95. Mass, E.; Wachten, D.; Aschenbrenner, A.C.; Voelzmann, A.; Hoch, M. Murine Creld1 Controls Cardiac Development through Activation of Calcineurin/NFATc1 Signaling. Dev. Cell 2014, 28, 711–726. [Google Scholar] [CrossRef] [PubMed]
  96. Redig, J.K.; Fouad, G.T.; Babcock, D.; Reshey, B.; Feingold, E.; Reeves, R.H.; Maslen, C.L. Allelic Interaction between CRELD1 and VEGFA in the Pathogenesis of Cardiac Atrioventricular Septal Defects. AIMS Genet. 2014, 01, 001–019. [Google Scholar] [CrossRef]
  97. Beckert, V.; Rassmann, S.; Kayvanjoo, A.H.; Klausen, C.; Bonaguro, L.; Botermann, D.S.; Krause, M.; Moreth, K.; Spielmann, N.; da Silva-Buttkus, P.; et al. Creld1 Regulates Myocardial Development and Function. J. Mol. Cell. Cardiol. 2021, 156, 45–56. [Google Scholar] [CrossRef]
  98. Asim, A.; Agarwal, S.; Panigrahi, I.; Sarangi, A.N.; Muthuswamy, S.; Kapoor, A. CRELD1 Gene Variants and Atrioventricular Septal Defects in Down Syndrome. Gene 2018, 641, 180–185. [Google Scholar] [CrossRef] [PubMed]
  99. Ghosh, P.; Bhaumik, P.; Ghosh, S.; Ozbek, U.; Feingold, E.; Maslen, C.; Sarkar, B.; Pramanik, V.; Biswas, P.; Bandyopadhyay, B.; et al. Polymorphic Haplotypes of CRELD1 Differentially Predispose Down Syndrome and Euploids Individuals to Atrioventricular Septal Defect. Am. J. Med. Genet. Part A 2012, 158, 2843–2848. [Google Scholar] [CrossRef]
  100. Robinson, S.W.; Morris, C.D.; Goldmuntz, E.; Reller, M.D.; Jones, M.A.; Steiner, R.D.; Maslen, C.L. Missense Mutations in CRELD1 Are Associated with Cardiac Atrioventricular Septal Defects. Am. J. Hum. Genet. 2003, 72, 1047–1052. [Google Scholar] [CrossRef] [PubMed]
  101. Kusuma, L.; Dinesh, S.M.; Savitha, M.R.; Krishnamurthy, B.; Narayanappa, D.; Ramachandra, N.B. A Maiden Report on CRELD1 Single-Nucleotide Polymorphism Association in Congenital Heart Disease Patients of Mysore, South India. Genet. Test. Mol. Biomark. 2011, 15, 483–487. [Google Scholar] [CrossRef]
  102. Guo, Y.; Shen, J.; Yuan, L.; Li, F.; Wang, J.; Sun, K. Novel CRELD1 Gene Mutations in Patients with Atrioventricular Septal Defect. World J. Pediatr. 2010, 6, 348–352. [Google Scholar] [CrossRef] [PubMed]
  103. Posch, M.G.; Perrot, A.; Schmitt, K.; Mittelhaus, S.; Esenwein, E.-M.; Stiller, B.; Geier, C.; Dietz, R.; Gessner, R.; Ozcelik, C.; et al. Mutations in GATA4, NKX2.5, CRELD1, and BMP4 Are Infrequently Found in Patients with Congenital Cardiac Septal Defects. Am. J. Med. Genet A 2008, 146, 251–253. [Google Scholar] [CrossRef]
  104. Williams, K.; Carson, J.; Lo, C. Genetics of Congenital Heart Disease. Biomolecules 2019, 9, 879. [Google Scholar] [CrossRef] [PubMed]
  105. Rykiel, G.; Gray, M.; Rongish, B.; Rugonyi, S. Transient Increase in VEGF-A Leads to Cardiac Tube Anomalies and Increased Risk of Congenital Heart Malformations. Anat. Rec. 2021, 304, 2685–2702. [Google Scholar] [CrossRef] [PubMed]
  106. Bi, Y.; Yang, Z.; Jin, M.; Zhai, K.; Wang, J.; Mao, Y.; Liu, Y.; Ding, M.; Wang, H.; Wang, F.; et al. ERp44 Is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium. Cell Prolif. 2022, 55, e13179. [Google Scholar] [CrossRef]
  107. Yan, L.; Ge, Q.; Xi, C.; Zhang, X.; Guo, Y. Genetic Variations of VEGF Gene Were Associated with Tetralogy of Fallot Risk in a Chinese Han Population. Genet. Test. Mol. Biomark. 2015, 19, 264–271. [Google Scholar] [CrossRef]
  108. Li, X.; Liu, C.L.; Li, X.X.; Li, Q.C.; Ma, L.M.; Liu, G.L. VEGF Gene Polymorphisms Are Associated with Risk of Tetralogy of Fallot. Med. Sci. Monit. 2015, 21, 3474–3482. [Google Scholar] [CrossRef]
  109. Wang, W.; Xu, A.; Xu, H. The Roles of Vascular Endothelial Growth Factor Gene Polymorphisms in Congenital Heart Diseases: A Meta-Analysis. Growth Factors 2018, 36, 232–238. [Google Scholar] [CrossRef]
  110. Reuter, M.S.; Jobling, R.; Chaturvedi, R.R.; Manshaei, R.; Costain, G.; Heung, T.; Curtis, M.; Hosseini, S.M.; Liston, E.; Lowther, C.; et al. Haploinsufficiency of Vascular Endothelial Growth Factor Related Signaling Genes Is Associated with Tetralogy of Fallot. Genet. Med. 2019, 21, 1001–1007. [Google Scholar] [CrossRef]
  111. Mcculley, D.J.; Kang, J.; Martin, J.F.; Black, B.L. BMP4 Is Required in the Anterior Heart Field and Its Derivatives for Endocardial Cushion Remodeling, Outflow Tract Septation, and Semilunar Valve Development. Dev. Dyn. 2008, 237, 3200–3209. [Google Scholar] [CrossRef] [PubMed]
  112. Bai, Y.; Wang, J.; Morikawa, Y.; Bonilla-Claudio, M.; Klysik, E.; Martin, J.F. Bmp Signaling Represses Vegfa to Promote Outflow Tract Cushion Development. Development 2013, 140, 3395–3402. [Google Scholar] [CrossRef] [PubMed]
  113. Nie, X.; Brown, B.; Wang, Q. Inactivation of Bmp4 from the Tbx1 Expression Domain Causes Abnormal Pharyngeal Arch Artery and Cardiac Outflow Tract Remodeling. Cells Tissues Organs 2011, 193, 393–403. [Google Scholar] [CrossRef] [PubMed]
  114. Li, F.F.; Deng, X.; Zhou, J.; Yan, P.; Zhao, E.Y.; Liu, S.L. Characterization of Human Bone Morphogenetic Protein Gene Variants for Possible Roles in Congenital Heart Disease. Mol. Med. Rep. 2016, 14, 1459–1464. [Google Scholar] [CrossRef]
  115. Qian, B.; Mo, R.; Da, M.; Peng, W. Common Variations in BMP4 Confer Genetic Susceptibility to Sporadic Congenital Heart Disease in a Han Chinese Population. Pediatr. Cardiol. 2014, 35, 1442–1447. [Google Scholar] [CrossRef]
  116. Zheng, S.; Chen, H.; Liu, X.; Yang, Q. Identification of Variants of ISL1 Gene Promoter and Cellular Functions in Isolated Ventricular Septal Defects. Am. J. Physiol. Cell Physiol. 2021, 321, C443–C452. [Google Scholar] [CrossRef]
  117. Yin, X.; Chen, H.; Chen, Z.; Yang, Q.; Han, J. Genetic Variants of ISL1 Gene Promoter Identified from Congenital Tetralogy of Fallot Patients Alter Cellular Function Forming Disease Basis. Biomolecules 2023, 13, 358. [Google Scholar] [CrossRef]
  118. Wang, Z.; Song, H.M.; Wang, F.; Zhao, C.M.; Huang, R.T.; Xue, S.; Li, R.G.; Qiu, X.B.; Xu, Y.J.; Liu, X.Y.; et al. A New ISL1 Loss-of-Function Mutation Predisposes to Congenital Double Outlet Right Ventricle. Int Hear. J. 2019, 60, 1113–1122. [Google Scholar] [CrossRef]
  119. Blue, G.M.; Kirk, E.P.; Giannoulatou, E.; Hil, D.P.; Sholler, G.F. Advances in the Genetics of Congenital Heart Disease: A Clinician’s Guide. J. Am. Coll Cardiol. 2017, 69, 859–870. [Google Scholar] [CrossRef] [PubMed]
  120. Bajolle, F.; Zaffran, S.; Bonnet, D. Genetics and Embryological Mechanisms of Congenital Heart Diseases. Arch. Cardiovasc. Dis. 2009, 102, 59–63. [Google Scholar] [CrossRef]
Table
Table 1. The contribution of different etiologic factors in the development of CHD (adapted after [5,6,7]).
Table 1. The contribution of different etiologic factors in the development of CHD (adapted after [5,6,7]).
Non-Genetic Contribution~10%Genetic Contribution~90%
Convincing evidence
-
Severe maternal obesity
Highly suggestive evidence
-
Antidepressants (lithium)
-
Maternal obesity
-
Maternal alcohol consumption
-
Maternal fever in the first trimester
Suggestive evidence
-
Antidepressants (SSRIs)
-
Paternal advanced age
-
Paternal smoking
Other
-
Retinoic acid
-
Anticonvulsants
-
Antiarrhythmics (class III)
-
Maternal diabetes mellitus
-
Maternal viral infections (rubella)
Aneuploidy (~13%)
-
Trisomy 21, 13 and 18
-
Monosomy X
CNV (~10%)
-
Del22q11.2
-
Del7q11.23
-
Del5p15.2
-
Del11q
-
Del8p23.1
-
Del1q21.1
-
Dup22q11
De novo mutations (~8%)
-
Chromatin-modifying genes
Transmitted mutations (~3%)
-
Transcription factors genes
-
Signaling molecules genes
-
Structural genes
Unknown (~56%)
CNV, Copy number variation; SSRI, selective serotonin reuptake inhibitor.
Table
Table 2. The milestones of cardiac development and the events leading to congenital heart defects (adapted with permission from [11]. 2013 Wiley Periodicals, Inc., Hoboken, NJ, United States).
Table 2. The milestones of cardiac development and the events leading to congenital heart defects (adapted with permission from [11]. 2013 Wiley Periodicals, Inc., Hoboken, NJ, United States).
Carnegie StageAge (DPC)EventsCHD
CS817–19Development of the heart-forming region
CS919–21Embryonic folding and placement of the heart-forming region in the final position
CS1022–23Formation of the heart tube
Looping
Ventricular ballooning
CS1123–26Atrial ballooning
CS1226–30Formation of the primary atrial septum
Development of the muscular part of the ventricular septumMuscular VSD
CS1328–32Formation of the atrioventricular cushions
Attachment of the pulmonary veins to the left atrium
CS1431–35Appearance of the outflow tract ridges
CS1535–38Formation of the secondary foramen
Beginning of the septation of the outflow tractTA, TGA, TOF
Migration of the neural crest cells to the outflow tractDORV, pulmonary atresia
CS1637–42Closure of the ostium primumAVSD, ASD I
Outflow ridges approaching the ventricular septum
CS1742–44Formation of the secondary atrial septumASD II
Separation of the atrioventricular communication
Completion of the outflow tract septationMembranous VSD
CS1844–48Formation of the atrioventricular valvesTricuspid atresia
ASD I, Atrial septal defect type ostium primum; ASD II, atrial septal defect type ostium secundum; AVSD, atrioventricular septal defect; CS, Carnegie stage; DORV, double-outlet right ventricle; DPC, days post-conception; TA, truncus arteriosus; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.
Table
Table 3. Genotype–phenotype correlation in TBX5 mutations.
Table 3. Genotype–phenotype correlation in TBX5 mutations.
Mutation TypeLocationCardiac PhenotypeOther PhenotypesReference
Nonsense—LOFc.577G>T (p.Gly193Ter)TAPVR and ASDTriphalangeal thumb[41]
Missensec.322C>A (p.Pro108Thr)Tricuspid atresia-[42]
Compound (missense +
nonsense)		c.791G>A + c.835C>T (p.Arg264Lys + p.Arg279Ter)HLHS, VSD and PDAHypoplastic thumb[43]
Missense—GOFc.373G>A (p.Gly125Arg)Early onset paroxysmal AF, ASD and VSD(Sub)luxation of the radial head, carpal synostosis, scoliosis and scapular dysplasia[44]
Missense—LOFc.668C>T (p.Thr223Met)Long QT syndrome, ASD and VSD-[45]
Nonsense—LOFc.835C>T (p.Arg279Ter)DCM, bicuspid aortic valve, and first-degree AV blockHypoplastic thumb[46]
Missense—LOFc.710G>A (p.Arg237Gln)DCM, ASD, sick sinus syndrome and AFMild pectus excavatum[46]
Microdeletion + microinsertionc.627delinsGTGACTCA GGAAACGCTTTCCT
GA		ASD and VSDBilateral dysplasia of radius and thumb[47]
Intragenic duplicationDup12q24.1—11 kb (exons 1–6)ASD, VSD and complete AV blockBilateral dysplasia of radius and thumb[48]
Intragenic duplicationDup12q24.21—48 kb (exons 2–9)AVSD, pulmonary stenosis, HLHS, atrial flutter, AF and sick sinus syndromeBilateral ulnar hypoplasia, syndactyly and fifth finger clinodactyly[49]
Contiguous deletionDel12q24.13-q24.21—3.1 Mb (including TBX5 and TBX3)ASD, VSD, right pulmonary artery hypoplasia and high-grade second-degree AV blockBilateral dysplasia of radius and thumb, fifth finger clinodactyly, absent nipples bilaterally, cryptorchidism and glandular hypospadias[50]
Contiguous duplicationDup12q24.21—399 kb (including TBX5 and TBX3)ASD, PDA, aortic stenosis, bicuspid aortic valve and AFAbsence of distal inter phalangeal joints of the thumb, hypoplastic thenar eminence, camptodactyly and supernumerary nipple[51]
AF, Atrial fibrillation; ASD, atrial septal defect; AV block, atrioventricular block; AVSD, atrioventricular septal defect; DCM, dilated cardiomyopathy; GOF, gain-of-function; HLHS, hypoplastic left heart syndrome; LOF, loss-of-function; PDA, patent ductus arteriosus; TAPVR, total anomalous pulmonary venous return; VSD, ventricular septal defect.
Table
Table 4. Genotype–phenotype correlation involving GATA4.
Table 4. Genotype–phenotype correlation involving GATA4.
Mutation TypeLocationCardiac PhenotypeOther PhenotypesReference
Missensec.431C>T (p.Ala144Val)Pulmonary atresia and ASD-[42]
Missensec.487C>T (p.Pro163Ser)ASDSexual development disorder[66]
Missensec.886G>A (p.Gly296Ser)VSD-[67]
Missensec.929T>C (p.Met310Thr)ASD, AVSD, pulmonary stenosis, AF, paroxysmal VT and junctional premature beat with aberrant ventricular conduction-[68]
Synonymousc.99G>T (p.Ala33Ala)ASD, VSD, coarctation of aorta and TOF-[69]
Synonymousc.822C>T (p.Cys274Cys)
c.906C>T (p.His302His)		Bicuspid aortic valve-[70]
SNP (regulatory variant)g.31360T>C
g.31436G>A
g.31437C>A
g.31487C>G
g.31856C>T		ASD-[71]
InsertionIns4+5G>ATOF-[42]
MicrodeletionDel8p23.1AVSDPsychomotor delay[42]
DeletionDelGATA4VSD, ASD and pulmonary stenosisCraniofacial dysmorphism and ectopic kidney[72]
DeletionDel8p23.1—between 2.945 and 6.352 MbDORV, AVSD, pulmonary atresia, TGA and ASDCongenital diaphragmatic hernia and craniofacial dysmorphism[73]
AF, Atrial fibrillation; ASD, atrial septal defect; AVSD, atrioventricular septal defect; DORV, double-outlet right ventricle; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect; VT, ventricular tachycardia.
Table
Table 5. Genotype–phenotype correlation involving NKX2-5 gene.
Table 5. Genotype–phenotype correlation involving NKX2-5 gene.
Mutation TypeLocationCardiac PhenotypeOther PhenotypesReference
Missensec.182C>G (p.Ala61Gly)VSD and coarctation of aorta-[87]
Missensec.284G>T (p.Arg95Leu)VSD-[87]
Missensec.391G>A (p.Glu131Lys)ASD and TOF-[87]
Missensec.443C>A (p.Ala148Glu)DORV, TGA, ASD, VSD, coarctation of aorta and atretic aortic valve-[87]
Missensec.739C>G (p.Pro247Ala)TOF-[87]
Missensec.413G>A (p.Arg138Glu)Familial ASD-[88]
Missensec.561G>C (p.Gln187His)Familial ASD-[88]
Missensec.355G>T (p.Ala119Ser)HLHS-[89]
SynonymousExon 2Septal defects-[90]
Nonsensec.541C>T (p.Gln181Ter)ASD and AV block-[91]
Nonsensec.574A>T (p.Lys192Ter)Bicuspid aortic valve-[92]
Frameshiftc.397-400delDORV, AVSD and TAPVRExtracardiac heterotaxy syndrome features[93]
ASD, Atrial septal defect; AV block, atrioventricular block; AVSD, atrioventricular septal defect; DORV, double-outlet right ventricle; HLHS, hypoplastic left heart syndrome; TAPVR, total anomalous pulmonary venous return; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.
Table
Table 6. Genotype–phenotype correlation involving CRELD1 gene.
Table 6. Genotype–phenotype correlation involving CRELD1 gene.
Mutation TypeLocationCardiac PhenotypeOther PhenotypesReference
Missensec.985C>T (p.Arg329Cys)AVSD, VSD and PPHT-[100,101]
Missensec.932C>T (p.Thr311Ile)AVSD-[100]
Missensec.320G>A (p.Arg107His)AVSD, pulmonary atresia, dextrocardia and right aortic arch (heterotaxy syndrome)-[100]
Missensec.973G>A (p.Glu325Lys)AVSDDown syndrome[98,102]
Missensec.857C>G (p.Pro286Arg)AVSD-[102]
Synonymousc.1628G>A (p.Lys336Lys)ASD-[103]
SNPc.-103G>T (5′UTR)ASD-[103]
SNPc.1048+23G>T (intronic)ASD-[103]
ASD, Atrial septal defect; AVSD, atrioventricular septal defect; PPHT, persistent pulmonary hypertension; SNP, single nucleotide polymorphism; UTR, untranslated region; VSD, ventricular septal defect.
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Bolunduț, A.C.; Lazea, C.; Mihu, C.M. Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review. Children 2023, 10, 812. https://doi.org/10.3390/children10050812

AMA Style

Bolunduț AC, Lazea C, Mihu CM. Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review. Children. 2023; 10(5):812. https://doi.org/10.3390/children10050812

Chicago/Turabian Style

Bolunduț, Alexandru Cristian, Cecilia Lazea, and Carmen Mihaela Mihu. 2023. "Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review" Children 10, no. 5: 812. https://doi.org/10.3390/children10050812

APA Style

Bolunduț, A. C., Lazea, C., & Mihu, C. M. (2023). Genetic Alterations of Transcription Factors and Signaling Molecules Involved in the Development of Congenital Heart Defects—A Narrative Review. Children, 10(5), 812. https://doi.org/10.3390/children10050812

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