Normal cardiac morphogenesis involves the migration and shape change of primordial cells, which require exquisite regulation of gene expression and a favorable microenvironment. Genetic lesions and environmental insults such as interstitial deletion of 8p32.1 to GATA4 gene, chemicals, viral infection, or nutritional deficiency would perturb the cardiac morphogenesis and result in axial extension defects [
7,
11]. This study investigated whether disease-causing CNVs exist in the five CHD fetuses.
Our data did not contain any known cardiac development genes although there could be as yet unidentified genetic contributors in these CNV regions. A unique 286,000 bp deletion region harbors DAAM1 and KIAA0666 genes on chromosome 14q23.1 in one isolated complex CHDs. The genes encode scaffolding proteins. Chromosome 14q23, a genetic locus linked to the left-sided CHD, contains genes important in the vascular endothelial growth factor (VEGF) signaling pathway, such as HIF-1, PGF, ACTN1, and EIF2, which have been implicated in the cardiac valve development [
4].
DAAM1 is one of the convergent-extension genes that regulates the actin cytoskeletal reorganization and plays a crucial role in CE movement of early vertebrate embryogenesis and later development [
12‐
14]. Apical actin bundles resulted from DAAM mutation have been found much shorter and thinner than those of the wild type, and crosslinked to each other, leading to the collapse of Drosophila tracheal system and discontinuity in the tubular network [
13]. Precursor cells towards heart development requires fibroblast growth factor and Wnt signaling pathway that can polarize the cytoskeleton [
15]. Vertebrate Wnt signals regulates RhoA-ROK/DAAM1 to control the acto-myosin network and physically interact with both Dsh and RhoA to regulate cell polarity and cell division via the polarity complex and the formin DAAM1 respectively [
16]. Via the Wnt/Fz/Dvl pathway, DAAM1 with RhoA participates in morphology and migratory behaviors in vertebrates such as cell fate specification, migration, proliferation and apoptosis [
13,
17]. Cardiac neural crest (cNC) passes through pharyngeal arches to the efferent pathway of the heart, and subsequent directional cell migration are essential for the formation of cardiac outflow tract [
18]. Failure of the cNC directed migration may cause severe defects in the conotruncal region and the atrioventricular septum. Earlier studies found that most heart abnormalities result from delayed migration or dysdifferentiation of the neural crest cells [
19]. Wnt signaling genes affect the myocardial development, and the cardiac epithelial mesenchymal transitions (EMT) relies on the Wnt/β-catenin signaling pathway [
14]. Rho proteins has been found for related cellular processes, for example EMT. DAAM1 is essential for Rho activation [
8]. The EMT plays a central role in the endocardial cushion morphogenesis, trabeculation and coronary system development, and it contributes to the development of mitral and tricuspid valve in the heart, as well as the maturation of interatrial and interventricular septa [
7]. Based on these earlier studies, we suggest that the deletion on 14q23.1 may have a previously unidentified effect on the cardiovascular development via mechanisms relating to the primordial cardiac cells and migrating cNC cells [
7]. Therefore, it is not unlikely that deletion of a single copy DAAM1, a member of the Wnt family, may be related to the causation of CHD in the fetus.
Although the role of gene dysregulation cannot be underestimated, given the complexity of heart malformations with low genetic risk in this case, the deletion of DAAM1 gene was unlikely to have produced such a profound effect. Occupational formaldehyde exposure may have contributed to the reproductive and developmental toxicity, although the potential mechanism is unclear [
20]. A variety of building materials and decoration materials such as paints, coatings and adhesives release formaldehyde, benzene, radon, and ammonia, which can cause indoor air pollution and negatively affect human health especially that of the developing fetus. Gases with teratogenic effects, such as those causing of cardiogenesis disruption in developing embryos, may alter the expression of certain developmental genes involved in Wnt or VEGF signaling [
4,
14]. However, this is largely hypothetical and the relationship can not be determined with certainty from this study.