**3. Etiology of congenital heart diseases**

The heart development, which initiates at embryonic day 15 in vertebrates, comprises an organized series of molecular and morphologic events that involve five primary steps: (1)

300-400 patients per year (Brown et al., 2009). These patients have elevated risk of premature morbidity and mortality. CHD is often more severe and has more complicated treatment in adults than children. Moreover, a recent analysis of the United States administrative database found that mortality was greater for adults with CHD when the operations were performed by adult cardiac surgeons, compared with pediatric (congenital-trained) heart surgeons (4.8% versus 1.9%, P<0.001) (Brown et al., 2009, as cited in Karamalou et al., 2008). For CHD adults, arrhythmias are more common, cardiac chambers often enlarge, and ventricles tend to develop systolic dysfunction. The main causes of death were progressive heart failure 26% and sudden

Table 3. The prevalence of adult CHD based on subtypes in year 2000, Canada (Marelli et al.,

Another problem that should be of concern is the transfer system from pediatric to adult health care. Many children with CHD did not follow-up when they were discharged from pediatric care and referred to adult care. In a Canadian study, only 47% of teenagers with CHD had transferred successfully to adult care (Reid et al., 2004). The results were similar in a German study, 76% of patients with CHD did not have follow-up care as an adult in a 5 year period (Wacker et al., 2005). The prevalence of adults with CHD is underestimated if it does not include this group of patients. These patients received medical care again when their diseases had progressed and their symptoms had become severe. This lack of care as an adult made it difficult to manage the disease and resulted in high morbidity & mortality in these patients. Patients with CHD must recognize the necessesity of ongoing surveillance

and the transfer system must be developed to prevent the loss of follow-up patients.

The heart development, which initiates at embryonic day 15 in vertebrates, comprises an organized series of molecular and morphologic events that involve five primary steps: (1)

cardiac arrest 22% (Zomer et al., 2010). Multidisciplinary care may also be required.

**Lesion prevalence per 1,000 adults** 

 TOF or truncus 0.17 AVSD 0.14 TGA 0.04 SV 0.03 All severe lesions 0.38

 ASD 0.88 VSD 0.78 PDA 0.02 AS or AR 0.11 Coarc 0.07 Ebstein's 0.01 All other lesions 3.71 All CHD 4.09

**3. Etiology of congenital heart diseases** 

Severe lesion

Other lesion

2007).

migration of pre-cardiac cells from the primitive streak and assembly of the paired cardiac crescents at the myocardial plate, (2) coalescence of the cardiac crescents to form the primitive heart tube, establishment of the definitive heart, (3) cardiac looping, assurance of proper alignment of the future cardiac chambers, (4) septation and heart chamber formation, and (5) development of the cardiac conduction system and coronary vasculature (McFadden & Olson, 2002; Moorman & Christoffels, 2003; Gittenberger-de Groot et al., 2005). From a series of complex processes, each component occurs at the right time under the orchestration of a cascade of genes and gene products, resulting in the coordination of cell migration and the formation of the extracellular matrix. Thus, CHD is usually caused by altered development of embryonic structure, or a failure of the structure to develop beyond an early embryonic or fetal stage. The anatomical defect generally influences further structural and functional development. Although descriptions of abnormal heart development in fetuses and babies have remained unclearly defined, substantial knowledge about the etiology of CHD have been made during the last decade. Some malformations may be directly inherited through vertical gene transfer, underlying the individuals' genetic disorder, or be associated with the consequences of an environmental toxin or diet. Alternatively, random errors in cell migration leading to improper cardiac development are possible. Together, the findings emphasize the complex and multifactorial causes of the CHD where additional research remain needed.

Better understanding for the etiology and risk factors of CHD is important, and will help pave the way for proper preventative measures and treatment guidelines by physicians as well as public health officers. The followings represent all reported potential causes of CHD to date.

#### **3.1 Genetic disorders**

The human genome, which contains approximately 20,000 to 25,000 genes, is comprised of coding and non-coding regions that are essential for proper protein structure and expression. The coding DNA sequence determines the amino acid sequence and subsequently the protein structure, and structure determines function (Lander, 2011; Reid-Lombardo & Bartelings, 2010). The non-coding sequences may contain promoters and regulation of transcription. In general, the DNA sequences remain relatively unchanged during vertical genetic transfer to the offspring. Nonetheless, occasional changes in the nucleotide sequences, referred to as mutations, and horizontal gene transfer do occur. Mutations range from a single nucleotide substitution, also called single nucleotide polymorphism (SNP), to a deletion or insertion of a DNA fragment. Some mutations only appear visible at the level of the chromosome (chromosome abnormalities), while some mutations cause phenotypic changes and a heritable trait to the offspring.

Any change in the DNA sequence, including SNPs, insertion, deletion and shuffling of DNA fragment, that results in frameshift mutation of the gene-encoding sequence likely affects protein folding and protein function. Abnormal protein folding structure and function can cause an improper development of many organs, including the heart. Hence, genetics is responsible for one major role in cardiovascular malformation, and indeed the genetic disorders represent the most common cause of CHD. Certain chromosome abnormities were linked to specific types of congenital heart lesions, and several types have been reported to be associated with specific gene defects. For instances, AVSD are often diagnosed in patients with trisomy 21.

 **TBX1, T-box 1 transcription factor, the T-box family;** The human TBX1 gene encodes another T-box transcription factor, expressed in neural crest and the developing cardiac outflow tract (conotruncus) (Calmont et al., 2009). Microdeletion TBX1 gene, located on chromosomal 22q11, causes DiGeorge syndrome, also known as Velocardiofacial syndrome. There are variable ranges of clinical phenotypes for DiGeorge syndrome, including IAA, truncus arteriosus, TOF, DORV and TGA (Jerome & Papaioannou, 2001;

 **TBX5, T-box 5 transcription factor, the T-box family;** is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. TBX5 was found expressed in embryonic human heart and limb. Mutations in this gene have been associated with Holt-Oram syndrome (Fan et al., 2003), which is characterized by skeletal malformations of the upper extremities and CHD, most commonly secundum ASD but also VSD and TOF (Basson et al., 1999; Faria et al., 2008; Li et al., 1997; Xin et

 **GATA4, GATA binding protein 4;** is related to zinc finger transcription factors. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function. Furthermore, GATA4 interacts with Tbx5 and with Nkx2-5 to regulate cardiac gene expression. This provides evidence that a transcriptional complex including all three proteins may be necessary for proper septation of the human heart. Mutations in this gene have been associated with non-syndromic CHD

 **TFAP2B, transcription factor AP-2 beta;** This gene encodes a member of the AP-2 family of transcription factors. This protein functions in the differentiation of neural crest cell derivatives, and contributes to the embryogenesis of the ductus arteriosus (Hilger-Eversheim et al., 2000). Mutations in this gene result in autosomal dominant Char syndrome, a dominant disorder comprised of facial dysmorphism, hand anomalies, and patent ductus arteriosus (Mani et al., 2005; Satoda et al., 2000; Zhao et

 **ZFPM2/FOG2, zinc finger protein, multitype 2;** The zinc finger protein encoded by this gene is a widely expressed member of the FOG family of transcription factors. The FOG family members modulate the activity of co-factors with the GATA family of proteins, which are important regulators of hematopoiesis and cardiogenesis in mammals. In experimental gene targeting of ZFPM2/FOG2 in mice, the mutation resulted in cardiac malformation including TOF, endothelial specific disruption (DORV, a common AV valve), VSD and ASD as well as left ventricular wall hypoplasia, and the failure to form coronary arteries (Tevosian et al., 2000). Recent reports found mutations of the ZFPM2/FOG2 gene associated with TOF (De Luca et

 **ZIC3, Zic family member 3 heterotaxy 1;** This gene encodes a member of the ZIC family of C2H2- type zinc finger proteins. Mutations in ZIC3 gene, located at chromosome Xq24-q27.1 (Casey et al., 1993), cause X-linked visceral heterotaxy and

cardiac septal defects (Gang et al., 2003; Tomita-Mitchell et al., 2007).

Stallmeyer et al., 2010).

al., 2009).

al., 2001).

al., 2010; Pizzuti et al., 2003).

Xu et al., 2004; Yagi et al., 2003).

CCVM. Although the contributions of these variants to the disease phenotype remains uncertain, the linkage between this gene disorder and the atrioventricular conduction defect, ASD, VSD or TOF, have been found (Elliott et al., 2003; McElhinney et al., 2003;

Moreover, CHD that occur in multiple members of a family increases the incidence of CHD in familial lines, and support evidences of inherited genetic disorders towards the heart abnormities. Molecular genetics in conjunction with cytogenetics provide an opportunity to decipher the genetic basis and pathogenesis of CHD. With the rapid era of DNA sequencing and genetic discoveries, it is expected that genetic diagnosis and screening will become incorporated into standard practice in the near future. Consequently, it is imperative that cardiologists understand the basis for genetic disorders, and the medical and ethical implications relevant to the genetic information. Today, genetics are predisposed to malformation of the hearts and blood vessels, and account for the highest number of human birth defects. Thus, hereditary and congenital diseases are classified into three broad categories
