Heart Malformation What Are the Chances It Could Happen Again?

Circulation (Impact Factor: 14.43). 08/2009; 120(4):269-71. DOI: 10.1161/CIRCULATIONAHA.109.878637
Source: PubMed
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    • "The incidence of CHD is 1% of all live births, although this is likely an underestimate as many anomalies do not require clinical intervention and remain undiagnosed (Mitchell et al., 2007; van der Bom et al., 2012). In addition to the estimated 40,000 new cases of CHD diagnosed in U.S. infants each year, it is estimated that at least another 40,000 individuals are born with undiagnosed heart defects that can contribute to disease later in their lives (Lau et al., 2011; Shieh and Srivastava, 2009). For example, undiagnosed abnormalities of atrioventricular valve development often result in valve deterioration and replacement surgeries in young adults (Nemer et al., 2008; Warnes et al., 2008). "
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    ABSTRACT: Congenital heart disease (CHD) is the most common birth defect. However, the majority of CHD cases have unknown etiology. Here we report the identification of ASXL2 and ASXL1, two homologous chromatin factors, as novel regulators of heart development. Asxl2-/- fetuses have reduced body weight and display congenital heart malformations including thickened compact myocardium in the left ventricle, membranous ventricular septal defect and atrioventricular valval stenosis. Although most Asxl2-/- animals survive to term, the neonates have patent ductus arteriosus and consequent lung hemorrhage and die soon after birth. Asxl1-/- fetuses have reduced body weight and display cleft palate, anophthalmia as well as ventricular septal defects and a failure in lung maturation. From these results, we conclude that normal heart development requires both ASXL proteins. In particular, ASXL2 plays an important role in heart morphogenesis and the transition from fetal to postnatal circulation. © 2014 Wiley Periodicals, Inc.
    genesis 07/2014; 52(7). DOI:10.1002/dvg.22793 · 2.02 Impact Factor
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    • "The influence of de novo changes on oligogenic disease is also unknown, however, it is possible that these genomic alterations combined with the effects of consanguinity could bring together the requisite components for disease. Furthermore, the epigenetic factors that contribute to CHD are largely unknown [Shieh and Srivastava, 2009], and it is unclear if consanguinity results in shared environmental contributions to disease. Different populations may be differentially susceptible to genetic and environmental perturbations , and it is important to continue these studies with a global perspective. "
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    ABSTRACT: Consanguineous unions have been associated with an increased susceptibility to various forms of inherited disease. Although consanguinity is known to contribute to recessive diseases, the potential role of consanguinity in certain common birth defects is less clear, particularly since the disease pathophysiology may involve genetic and environmental/epigenetic factors. In this study, we ask whether consanguinity affects one of the most common birth defects, congenital heart disease, and identify areas for further research into these birth defects, since consanguinity may now impact health on a near-global basis. A systematic review of consanguinity in congenital heart disease was performed, focusing on non-syndromic disease, with the methodologies and results from studies of different ethnic populations compared. The risks for congenital heart disease have been assessed and summarized collectively and by individual lesion. The majority of studies support the view that consanguinity increases the prevalence of congenital heart disease, however, the study designs differed dramatically. Only a few (n = 3) population-based studies that controlled for potential sociodemographic confounding were identified, and data on individual cardiac lesions were limited by case numbers. Overall the results suggest that the risk for congenital heart disease is increased in consanguineous unions in the studied populations, principally at first-cousin level and closer, a factor that should be considered in empiric risk estimates in genetic counseling. However, for more precise risk estimates a better understanding of the underlying disease factors is needed.
    American Journal of Medical Genetics Part A 05/2012; 158A(5):1236-41. DOI:10.1002/ajmg.a.35272 · 2.16 Impact Factor
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    ABSTRACT: Somatic mutations and dysregulation by microRNAs (miRNAs) may have a pivotal role in the Congenital Heart Defects (CHDs). The purpose of the study was to assess both somatic and germline mutations in the GATA4 and NKX2.5 genes as well as to identify 3'UTR single nucleotide polymorphisms (SNPs) in the miRNA target sites. We enrolled 30 patients (13 males; 13.4±8.3 years) with non-syndromic CHD. GATA4 and NKX2.5 genes were screened in cardiac tissue of sporadic and in blood samples of familial cases. Computational methods were used to detect putative miRNAs in the 3'UTR region and to assess the Minimum Free Energy of hybridization (MFE, kcal/mol). Difference of MFEs (ΔMFE)≥4 kcal/mol between alleles was considered biologically relevant on miRNA binding. The sum of all ΔMFEs (|ΔMFEtot| =∑|ΔMFE|) was calculated in order to predict the biological importance of SNPs binding more miRNAs. No evidence of novel GATA4 and NKX2.5 mutations was found both in sporadic and familial patients. Bioinformatic analysis revealed 27 putative miRNAs binding to identified SNPs in the 3'-UTR of GATA4. ΔMFE ≥4 kcal/mol between alleles was obtained for the +354A>C (miR-4299), +587A>G (miR-604),+1355G>A (miR-548v, miR-139-5p) and +1521C>G (miR-583, miR-3125, miR-3928) SNPs. The +1521C>G SNP showed the highest ΔMFEtot (21.66 kcal/mol). Luciferase reporter assays indicated that miR-583 was dose-dependently effective in regulating +1521 C allele compared with +1521 G allele. Based on the analysis of 100 CHD cases and 204 healthy newborns, the +1521 G allele was also associated with a lower risk of CHD (OR=0.5, 95% CI 0.3-0.9, p=0.03), likely due to the relatively low binding of the miRNA and high levels of protein. These results suggest that common SNPs in the 3' UTR of GATA4 alter miRNA gene regulation contributing to the pathogenesis of CHDs.
    Journal of Molecular and Cellular Cardiology 04/2013; 60(1). DOI:10.1016/j.yjmcc.2013.04.002 · 4.66 Impact Factor
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