An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects

Division of Cardiovascular Medicine and the Heart Research Center, Oregon Health & Science University, Portland, OR 97239, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 10/2012; 91(4):646-59. DOI: 10.1016/j.ajhg.2012.08.017
Source: PubMed


About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.

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    • "In addition, we examined Frzb mRNA, which encodes a secreted antagonist of WNT signalling that is required for atrioventricular cardiac cushion development in the chicken (Person et al., 2005). Furthermore, mutation of FRZB has been associated with one case of atrioventricular septal defect in humans (Ackerman et al., 2012). Interestingly , murine Frzb expression decreases in the absence of Tbx1 in vivo (Liao et al., 2008) and is upregulated when Tbx5 is overexpressed in mouse cardio fibroblasts (Zhou et al., 2012). "
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    • "However similar to previous studies, Vegf-a mRNA levels were increased in diabetic fetal hearts [35]. Elevated expression levels of VEGF-A are associated with congenital heart defects [46,47]. High VEGF-A levels in fetal hearts inhibit epithelial-to-mesenchymal transition (EMT) in the endocardial cushion, which contributes to formation of atrioventricular septum [48,49]. "
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    ABSTRACT: Pregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes. Female mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed. Our data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment. Treatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes.
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    • "substrate adhesion in the H9C2 cell line. Recent studies also suggest the potential contribution of VEGFA (Ackerman et al. 2012), ciliome and Hedgehog (Ripoll et al. 2012), and folate (Locke et al. 2010) pathways to the pathogenicity of CHD in DS. There are also several mouse models for partial or complete trisomy syntenic to human chromosome 21 (Sago et al. 1998; Shinohara et al. 2001; Dunlevy et al. 2010; Yu et al. 2010). "
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