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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 3  |  Page : 210-220

The genetic architecture behind congenital heart disease: A review of genetic and epigenetic factors

Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America

Date of Submission02-Oct-2021
Date of Decision25-Nov-2021
Date of Acceptance16-Jan-2022
Date of Web Publication08-Jul-2022

Correspondence Address:
Maaged A Akiel
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, P. O. Box: 22490 Riyadh 11481

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jnsm.jnsm_126_21

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Congenital heart disease (CHD) is the most frequently reported cause among miscarriages. Moreover, Infants born with CHD suffer from lifelong morbidity and have high risk of sudden infant death. The incidence of CHD is 8:1000, around 1% of live births worldwide. A wide range of environmental risk factors such as exposure to teratogens increase the risk for CHD through alterations in genetic and epigenetic networks governing heart development. Yet, a small subset of CHD is caused by inherited Mendelian mutations, copy number variations, or chromosomal abnormalities. Next generation sequencing technologies and chromosomal microarray analysis deciphered the genetic make-up of CHD. This review explains the genetic make-up of CHD and highlights key molecular genetics, cytogenetics, and epigenetics findings in syndromic and isolated CHD through analysis of inherited and sporadic genomic alterations.

Keywords: Congenital heart disease, epigenetic factors, genetic factors

How to cite this article:
Akiel MA. The genetic architecture behind congenital heart disease: A review of genetic and epigenetic factors. J Nat Sci Med 2022;5:210-20

How to cite this URL:
Akiel MA. The genetic architecture behind congenital heart disease: A review of genetic and epigenetic factors. J Nat Sci Med [serial online] 2022 [cited 2022 Aug 17];5:210-20. Available from: https://www.jnsmonline.org/text.asp?2022/5/3/210/350293

  Introduction Top

Congenital heart disease (CHD) is a structural abnormality of the heart and great vessels that originate from developmental defects during embryogenesis.[1] CHD is the most common birth anomaly in the newborn and is the most common structural anomaly of the heart and blood vessel manifesting in approximately 0.8% to 1% of live births.[1] The prevalence and severity of CHD vary geographically as observed by an increase in prevalence among economically poor countries or countries with high consanguinity.[2],[3] For example, in the Kingdom of Saudi Arabia, the prevalence of CHD was reported to be between 2.1 and 10.7 per 1000 live births.[4] Pathologically, the disease is classified into conotruncal defects (CTD) affecting the ventricular septum and outflow tract, defects in the left-right relationships (Heterotaxy), defects in the atrioventricular canal affecting the mitral and tricuspid valves and a wide range of isolated atrial or ventricular septal defects (VSD) [Figure 1].[5] An example of geographical variation in CHD severity is observed in Saudi Arabia where 40.2% of CHD patients suffer from severe abnormalities while only 33% of CHD patients in Norway are considered severe. Severe abnormalities observed in Saudi Arabia and Norway include VSD, univentricular hearts, atrioventricular canal defects (AVCs), heterotaxy, CTD, total anomalous pulmonary venous return, left ventricular outflow defects, and right ventricular outflow defects. CHD patients with such severe phenotype must receive surgical treatment in the 1st year after birth.[3],[6] Moreover, patients with CHD present with cardiac and noncardiac symptoms.[7] Unfortunately, with such adverse effects, CHD is ranked as the main cause of death from birth defects worldwide.[1] Although the incidence of CHD does not seem to be gender specific, males tend to have higher incidence of serve CHD than females as observed by an increase in mortality by 5% in males compared to females.[8],[9] Symptoms of CHD include dyspnea, i.e., shortness of breath, heart murmur, loss of consciousness, failure to thrive, and cyanosis, i.e., bluish discoloration of the skin. The symptoms of CHD can be syndromic, i.e., frequently associated with extracardiac developmental defects such as intellectual disability, neurodevelopmental delays, and craniofacial developmental delays or it can be isolated, i.e., stand-alone symptoms.[10] The etiology of CHD is not well understood and is considered to be complicated as only 35% of CHD cases were clinically ascertained to genetic alterations that cause familial CHD, i.e., genetic alterations segregate in families or cause sporadic CHD, i.e., de novo alterations that do not run in families.[11] The remaining 65% of CHD cases are multifactorial that include environmental factors such as prenatal infections, maternal health, and teratogenic factors or of unknown etiology.[11] Collectively, all these factors contribute to the complexity of genotype-phenotype associations in CHD.[12] This review will explain the genetics behind CHD and will list current genetic and epigenetic alterations that are highly associated with the disease pathology.
Figure 1: Classification of congenital heart defects: Schematic diagram of classification of congenital heart defects according to structural abnormalities. Teratology of fallot, transposition of the great arteries, double-outlet right ventricle, bicuspid aortic valve, supravalvular aortic stenosis, hypertrophic cardiomyopathy

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  Molecular Development of the Heart Top

Development of the heart starts early in embryogenesis between day 18 and 19 of gestation at which the formulations of 3 germline layers ectoderm, mesoderm, and endoderm are completed.[13] Mesodermal cells initiate the development of the fetal cardiac tissue at day 15 of embryogenesis after that neural crest cells bind the formed cardiac tissue. Eventually, the formation of endocardial tube is completed at day 19, the start day of development of a fully structured heart.[13] At day 21, cardiac myocytes proliferate with high cellular turnover. As a result, the endocardial tubes are merged to form a single tube. By day 23, a series of stretching and looping follows to lead to the formation of fully structured fetal heart by day 28.[13] This time-sensitive complex process is orchestrated by expression of series of transcription factors (TFs) and molecular signaling pathways.[13] The expression of cardiac-specific TFs starts with Islet1 and NKX2.5 in the cardiac crescent (mesodermal cells). Next, neural crest (ectodermal cells) secretes BMB inhibitors which regulate the expression of FGF in mesodermal cells of the developing heart to define the posterior border of the heart and form primitive cardiac myocytes.[13] The WNT/β-catenin pathway plays a major role in the formation of primitive cardiac myocytes through increasing cellular proliferation of primitive cardiac cells in the mesoderm.[13] Upon completion of the proliferation cycle of primitive cells, Islet1 and NKX2.5 are then downregulated.[13] The cardiac-specific T-box family of TFs (TBX1-20) plays pivotal roles in cardiomyocytes lineage commitment and heart patterning. They are expressed in nearly all parts of the heart. For example, TBX1 is expressed in outflow tract of the heart and regulates patterning of the inflow-outflow poles.[13] TBX5 and TBX20 induce ventricular cardiac chamber program gene expression to regulate chamber formation, while TBX2 and TBX3 act as repressors of ventricular myocardium gene program to allow the development of the atrioventricular part of the heart.[13] A number of other regulatory genes and TFs participate in the development of the heart, reviewed in Buijtendijk et al.[13] Hence, the structure and function of the heart are fine-tuned by the activity of these cardiac-specific genes. Nearly, expression of all cardiac-specific genes is sensitive to dosage. Therefore, alterations in any of these genes would affect dosage and would probably have adverse effects on development of the heart.

  The Genetic Component of Congenital Heart Disease Top

Despite the multifactorial etiology of CHD, genetics plays a major role in the pathogenesis of CHD.[11] The observed variations in incidence and risk of development of CHD among individuals from different ancestral backgrounds suggest that genetics plays a role.[14] The recurrence of CHD in multiple families where familial segregation of the disease is observed in affected family members suggests a genetic component to CHD. For example, the recurrence risk ratio of acquiring another offspring with CHD in a family with familial segregation of the disease could increase to 79.1 depending on the type of inherited allele and severity of the disease.[15] Moreover, a metanalysis of four twin studies found a nine-fold risk increase of CHD in monozygotic twin pairs compared to dizygotic twin pairs.[16] Furthermore, increased concordance of CHD was reported in monozygotic twins compared to dizygotic twins.[17] Monozygotic twins are genetically 100% identical while dizygotic twins are 50% identical. When the concordance of a certain disease is higher in monozygotic twin pairs than dizygotic twin pairs, the implication of genetics to the trait increases.[18] Therefore, genetics certainly plays a significant role in CHD. This congenital morbidity is classified into syndromic and isolated (nonsyndromic). Most CHD cases are isolated CHDs that arise from sporadic (de novo) genetic alterations, however, there is subset of mendelian (inherited) types of CHD as observed by the increased incidence of CHD in populations with high consanguinity.[3] Genetic alterations that underlie the development of CHD include chromosomal aneuploidies, copy number variations (CNVs), and single nucleotide variations (SNVs).[19] All these genetic alterations contribute to syndromic and isolated CHDs.[19] Syndromic and isolated CHDs are genetically different as isolated CHDs harbor mutations that are mostly inherited from unaffected parents while syndromic CHDs are de novo mutations.[20] In addition, large proportion of cases is isolated CHDs.[11] Monoallelic mendelian types of CHD account for a small number of reported cases.[5],[11] Such high-effect variants are rare in the population due to natural selection as a result of their severity on gene structure, phenotype, and possibly reproductive fitness.[21] Mutations in TFs are mostly detected in mendelian types of CHD and these include high-effect mutations in NKX2-5 causing atrial septal defects (ASD),[22] heterotaxy by mutation in ZIC3,[23] severe mitral valve prolapse due to mutations in LMCD1 and DCHS1, respectively,[24],[25] and NOTCH1 mutations in bicuspid aortic valve (BAV).[26] The genotype-phenotype association in sporadic CHD is not as simple as in monoallelic mendelian forms of isolated CHD. Examination of family pedigree and family trios with next-generation sequencing (NGS) technology facilitated the identification of causative variants in familial monogenic CHD.[5] Analysis of sequencing data from 154 families with familial CHD identified CHD pathogenic variants in 10% of studied families. Highest number of variants were identified in genes encoding TFs NKX2-5 and ZIC3.[27] Since the majority of CHD cases are sporadic, increased number of confounders makes the genotype-phenotype association a challenging task.[11] CHD is a heterogeneous disease and confounders in CHD include low-effect polygenic variants, low penetrant variants, gene-gene interaction (epistasis), and gene-environment interaction. In addition, gene dosage also controls the phenotype.[5],[11] Some gene variants are low-effects on gene dosage and therefore will not have adverse effects on heart development and will appear to skip a generation in the family pedigree (low penetrant) or have late-onset disease (appearing later in life) due to gene-environment interactions.[5],[11] Other gene variants are high-effect on gene dosage resulting in haploinsufficiency, which means that one defective allele alters the dosage of gene expression, hence affect gene function and cardio-developmental programs. Gene-gene interaction is when alteration or depletion of a gene product affects the function of another gene or ultimately a pathway that regulates molecular cardiac developmental programs. As a result, low-effect variants from multiple genes that are in the same signaling pathway will have a summative high-effect on the molecular development of cardiac tissue. Therefore, it crucial to cluster identified variants according to their signaling pathways or molecular networks to fully understand summative effects of low-effect variants to accurately identify causative variants contributing to CHD. Whole genome sequencing and whole-exome sequencing (WES) of CHD patients using NGS technologies and molecular pathway analysis ushered new information that helped in untangling the complexity of CHD, especially with identification and interpretation of de novo variants with no clear mendelian inheritance, variants of reduced penetrance, and somatic mutations.[12] This area of investigation is largely unexplored as much more interpretations are needed to clinically translate the heterogeneity of CHD into practice.

  Established Genetic Effects in Congenital Heart Disease Top

Chromosomal aneuploidy (syndromic congenital heart disease)

Cytogenetic anomalies were one of the first reported cases contributing to CHD. Aneuploidy accounts for 9% to 18% of the CHD cases.[28] Due to alteration of large genomic segments, nearly all cases are pleiotropic and severe with 98% of fetuses have a minimum of one extracardiac phenotype.[11] Numerical chromosomal alterations that are frequently associated with CHD include trisomy 21, trisomy 18, trisomy 13, and monosomy X.[28]

Trisomy 13 (Patau syndrome)

A rare numerical chromosomal abnormality characterized by a gain of an additional chromosome 13. The incidence of Patau syndrome is 1:5000 live births. Trisomy 13 is ranked third in frequency of chromosomal aneuploidy in live births.[29] However, most patients with trisomy 13 die within a year after birth due to multiorgan congenital abnormalities.[29] The syndrome is caused by maternal meiotic nondisjunction errors. A small subset of trisomy 13 can result from unbalanced Robertsonian translocations.[29] Approximately 60% of patients with Patau syndrome suffer from CHD.[28] Cardiac abnormalities include VSD (42% of CHD), patent ductus arteriosus (PDA; 57% of CHD), ASD (85% of CHD), and other complications of CHD such as coarctation of the aorta, and dextrocardia (heart toward the right side). Extracardiac abnormalities include microcephaly (small head circumference), microphthalmia (small eyes), clift lip/palate, postaxial polydactyly (extra ulnar or fibular fingers), and renal abnormalities.[29] This syndrome is detected by noninvasive prenatal testing (NIPT), amniocentesis, or chorionic villus sampling (CVS). Fluorescent in situ hybridization and comparative genomic hybridization is commonly used molecular techniques to detect numerical abnormalities in amniocentesis and CVS samples, respectively. On the other hand, NGS platforms are used to detect chromosomal abnormalities in NIPT blood samples with great accuracy for trisomy 13.[29] Molecular pathway analysis and gene ontology analysis of chromosomal microarray data from patients with trisomy 13 revealed a gain in FOXO1 and several other genes in chromosome 13 that have trans transcriptional regulatory functions on cardiac associated genes in other chromosomes.[30] Implications of other genes or regulatory networks that are altered by chromosomal gains have not been discovered yet due to reduced survival and rarity of the syndrome.

Trisomy 18 (Edwards syndrome)

A numerical chromosomal abnormality characterized by a gain of an additional chromosome 18 altering the expression of a plethora of highly regulated genes. The incidence of Edwards syndrome was reported to be 1:6000 live births. Trisomy 18 is ranked as the second chromosomal aneuploidy in frequency of live births. Like trisomy 13, Edwards syndrome is also caused by maternal nondisjunction errors or to a lesser extent by unbalanced translocations.[29] Patients with Edwards syndrome have multiple phenotypes which include growth retardation, neurodevelopmental abnormalities, “rocker-bottom” feet. Almost 80% of patients with Edwards syndrome present with CHD.[28] Cardiac abnormalities include VSD (94% of cases), PDA (88% of cases), and ASD (76% of cases) and other abnormalities, reviewed in Witters et al.[29] As all numerical chromosomal, trisomy 18 can be accurately diagnosed with NIPT, CVS, and amniocentesis.[29] A previous study on chromosome 18 helped to define the gene architecture of the chromosome and hence defined genes affected by dosage.[31] Subsequent studies found that there are more than 251 genes that were differentially expressed in patients with Edwards syndrome with only 2.8% found in chromosome 18.[32] A more recent study identified that although not located in chromosome 18 several genes were downregulated in trisomy 18 patients and were probably associated with cardiac developmental programs.[33] These genes include TBX4, NOG (BMP signaling inhibitor), MAF, MYO1D, ISL2, TBX1. All these genes were implicated in the development of cardiac and skeletal muscles in the literature.[13] All these reports suggest that alterations of gene dosage in chromosome 18 affected gene expression of nonchromosome 18 genes.

Trisomy 21 (Down syndrome)

Down syndrome (DS) is the most common chromosomal aneuploidy achieving an incidence of 1:700 with a recurrence rate of 1%. Furthermore, it is the most common cause of cardiac abnormalities as it contributes to more than 60% of liveborn cases that present with congenital CHD.[29] Like trisomy 13 and 18, it is caused by a meiotic maternal nondisjunction error. A small subset of trisomy 21 (4%) is due to balanced Robertsonian translocation between chromosome 13 or 14 and 21 from paternal side.[29] Phenotypically, patients with DS are characterized by flattened nasal bridge, upslanted palpebral fissures, brachycephaly, and CHD. Cardiac malformations include ASD, VSD, and AVC.[29] Patients with mosaic trisomy 21 in heart tissue also present with CHD. Molecular analysis of mosaic and full trisomy 21 patients revealed alteration in genes implicated in the molecular cardiac development network.[34] Reported mutations in DS include GATA3, KCNH2, ENG, FLNA, and GUSB genes and gene duplications, dosage effect, in DSCAM, KCNJ6, RCAN1, and COL6A.[34],[35] All these mutations are causative factors for CHD observed in DS and mosaic trisomy 21 patients.

Monosomy X (Turner syndrome)

Turner syndrome is characterized by loss of chromosome X in females. The incidence of monosomy X is 1:2500 live female births. More than 50% of turner syndrome cases are presented either as mosaic, mixed cells with 46, XX and 45, X or as an isochromosome X I (Xp) or I (Xq).[29] The karyotype 45, X is present in <50% of the cases. Patients with Turner syndrome are short in stature, infertile, and present with webbed neck. Only 33% of cases with monosomy X present with CHD, which include BAV, aortic dilatation coarctation of aorta, and aneurysm.[28],[36] Compared to females, males have only one X chromosome and therefore during fetal embryonic development the additional X chromosome in females needs to be inactivated to maintain gene dosage equilibrium between males and females through epigenetic regulation called “X-inactivation.” As a result, the loss of an X chromosome in females alters this dosage compensation and is thought to be responsible for the cardiac phenotype in Turner syndrome patients.[37] Altered dosage of SHOX (short stature homeobox-containing gene) is responsible for short stature observed in Turner syndrome patients. SHOX is a TF that its target genes include brain natriuretic peptide and fibroblast growth factor receptor 3. Both genes were implicated in cardiac development.[38] Moreover, altered expression of PAR 1 and PAR2 was also observed in Turner syndrome patients and was linked to cardiovascular disease.[37] The list of genes contributing to CHD due to altered dosage in chromosome X is increasing as more studies are being conducted.

Copy number variations

CNVs are genomic structural variations that consist of deletions and duplication of genomic segments in a chromosome ranging in size from couple of base pairs to a couple of megabases.[5] Such changes in the genome lead to perturbations in dosage of expressed genes.[5] CNVs could arise as de novo events or can be inherited from parents.[5] A couple of reported large CNVs have been defined to cause a number of clinical syndromes that manifest with CHD.[5] For example, Del22q11 known as DiGeorge syndrome, a deletion of 3-mega base considered to be the most common microdeletion in humans.[39] The deleted region encompasses the TBX1 gene that its haploinsufficiency has been reported to cause the cardio-pharyngeal phenotype in patients with DiGeorge syndrome.[39] Other well-defined CHD associated CNVs [Table 1] include Del8p23 (includes GATA4 gene), Del7q11, known as Williams syndrome (includes ELN gene), Del11q24-25, known as Jacobsen syndrome, deletions 1q21.1, 3p25.1, 16p13.11, 15q11.2, and 2p13.3.[40],[41] CNVs in the region of 22q11.2 encompassing GATA4, NKX2-5, TBX1, TBX5, BMP, and CRELD1 have been reported to cause sporadic CHD and several other CNVs in other regions been reported in [Table 1].[40],[42]
Table 1: Known copy number variations contributing to congenital heart disease

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Inherited mendelian forms of congenital heart disease

In mendelian forms of CHD, the pathogenic variants are mostly found in genes associated with cardiac development at which they contribute to isolated forms of CHD.[5],[20] Inherited point mutations in cardiac-specific genes account for approximately 2% of CHD cases.[11] Large numbers of cardiac-associated gene variants in monogenic forms of CHD belong to family of TFs regulating cardiac developmental programs such as GATA family of zinc-finger proteins, TBX5, TBX1, and MEF2 TFs. One of the first inherited mutations in CHD was identified in NX2.5.[43] NX2.5 is a TF that works in mesodermal cells during heart development in conjunction with GATA4.[5] These mutations often result in haploinsufficiency, which can affect binding of NX2.5 to the promoter region of target genes thereby altering their gene expression.[5] Mutations in NX2.5 are heterogenous and cause autosomal dominant VSD.[44] Patients with these mutations manifest with ASD and the phenotype can include VSD, teratology of fallot, Supravalvular Aortic Stenosis, and others.[45] Similarly, mutations in GATA4 cause autosomal dominant ASD disorder.[46] Mutations in GATA4 diminishes its binding affinity to regulatory elements in target genes where it works in conjunction with TBX5.[46] Therefore, it is not surprising to see that mutations in TBX5 would also cause the phenotype of ASD and VSD in patients with autosomal dominant Holt-Oram syndrome.[47] ZIC3 is a zinc finger TF that regulates functional left-right organization of the heart, hence, X-linked mutations in ZIC3 were identified in patients with complete situs inversus and complete situs solitus.[48] After the availability of NGS platforms, testing of familial forms of CHD would be a straightforward task, especially when family history, and family pedigrees are available. The targeted gene can be easily identified by examining family trios. A list of other familial mutations are provided in [Table 2] and [Table 3].
Table 2: Updated list of classified variants contributing to isolated congenital heart disease

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Table 3: List of known genes contributing to syndromic congenital heart disease

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Single nucleotide variations contributing to congenital heart disease

Classical linkage analyses and positional cloning facilitated the identification of causative high effect gene mutations contributing to isolated CHD.[10] Pathogenic SNVs that were associated with isolated CHD cases include NKX2-5, NKX2-6, TBX20, GATA4, GATA5, GATA6, ZIC3, PITX2, MYH6, JAG1, and NOTCH2 [Table 2].[41] All these genes are key TFs and signaling molecules regulating cardiac development, therefore, mutations in such genes are of high effect.[41] On the other hand, syndromic SNVs such as mutations in RAS pathway genes that are strongly associated with CHD overlap with extracardiac phenotype as observed in Noonan syndrome. Other syndromic SNVs include Adam-Oliver syndrome (mutations in ARHGAP31, DOCK6, RBPJ, and EOGT genes), Holt-Oram syndrome (mutation in TBX5 gene), Kabuki syndrome (mutation MLL2 gene), CHARGE syndrome (mutation in CHD7 gene), and Koolen-De Vries syndrome (mutation KANSL1 gene) [Table 3].[41] The list of syndromes and isolated SNVs contributing to CHD will keeping increasing as causative variants are identified using NGS technologies of probands and affected families.

Epigenetic alterations contributing to congenital heart disease

WGS of CHD cohorts has furnished substantial evidence for the presence of pathogenic variant in regulatory elements outside of gene exons (coding region). Epigenetic alterations and mutations in chromatin remodeling genes were significantly associated with CHD.[5] These alterations mediate blocking cardiac TFs from binding to transcription start sites or can alter expression of TFs by facilitating the heterochromatin formation through increasing the methylation of histones (subunits of chromatin), reviewed in Jarrell et al.[49] Hypermethylation of NKX2.5 and HAND1 TFs were reported in CHD patients.[49] Moreover, analysis of CHD using twin studies revealed hypermethylation of more than 120 genes because of epigenetic dysregulation. Hypermethylated TFs in twins with CHD include ZIC3 and NR2F2.[49] In addition, perturbations in posttranslation modifications of histones were reported in patients with CHD, posttranslation modifications are reviewed in Jarrell et al.[49] For example, defects in HDAC2 and HDAC3 (histone deacetylase enzymes) alter expression of GATA4 and TBX5 TFs, which affect development of the heart. Another level of epigenetic regulation that cardiac cells use to regulate expression of cardiac gene programs involves long-noncoding RNAs (lncRNA) and small noncoding RNAs (miRNA), reviewed in Jarrell et al.[49] Several studies that use animal models to analyze cardiac cell development showed that altering the expression of miR-1-1 and miR-1-2 affected cardiac cell differentiation through deregulation of MEF2 and HAND2, key TFs regulating cell differentiation.[49] The area of epigenetic alteration in CHD is largely unexplored. Clinically, these alterations yet to be included in diagnostic panels for CHD as more research utilizing functional analysis tools and validation in animal models is needed.

Concluding remarks

Identification of novel genetic and epigenetic alterations contributing to the development of CHD increased our understanding of the pathogenesis of this anomaly. The huge influx of data coming out of NGS pipelines significantly increased the pool of variants that are etiologically associated with the phenotype. This runs in parallel with the increased complexity observed in CHD as more potential loci are being detected. Appropriate correlation of the genotype to the phenotype is a fundamental step in the translation of genomics findings to have any diagnostic value. Despite this remarkable success in correlation studies that helped in dissecting the genomic variation in CHD, only small subsets of CHD cases are solved using the “only genetics” approach. Several system biology studies have pointed out that CHD is a multifactorial disease rather than single molecular genetic disease.[50],[51] Multiple environmental risk factors affected protein function and biological networks that control heart development rather than a single molecular genetic signature.[50] These studies provided thorough evidence of a gene-environment interactions driving pathogenesis of CHD. Such findings limit our current detection rate that we can pump out of NGS platforms. Therefore, to increase detection of CHD, a more comprehensive platform using data from NGS, systems biology, molecular pathway analysis, and proteomics need to be included. This can be achieved by utilizing bioinformatic tools that develop a comprehensive database that can smoothly integrate risk factors of CHD and their functional effects of developmental networks of the heart to increase our detection rate of CHD using our currently available technologies.

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Conflicts of interest

There are no conflicts of interest.[62]

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  [Table 1], [Table 2], [Table 3]


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