Genetics of Congenital Heart Disease: The Glass Half Empty

Department of Genetics, NRB Room 256, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA 02115. .
Circulation Research (Impact Factor: 11.02). 02/2013; 112(4):707-20. DOI: 10.1161/CIRCRESAHA.112.300853
Source: PubMed


Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.

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    • "Till date, more than 10 genes that encode transcription factors or cofactors (NKX2.5, GATA4, TBX5, TBX20, and CITED2), structure proteins of the sarcomere (ACTC1, MYH6, MYH7, and MYBPC3), and a metalloprotease (TLL1) have been implicated in inherited ASD (Wessels and Willems, 2010; Fahed et al., 2013). "
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    ABSTRACT: The GATA-binding protein 4 gene (GATA4) encodes a zinc-finger transcription factor that plays a key role in embryogenesis and cardiac development. Variants in the GATA4 gene have been implicated in several congenital heart diseases (CHD), such as the tetralogy of Fallot (ToF), atrial septal defect (ASD), ventricular septal defect (VSD), atrioventricular septal defect (AVSD), and dilated cardiomyopathy (DCM). We studied a four-generation Chinese ASD family and identified a novel GATA4 mutation (c.A899C, p.K300T) in all surviving affected members and two carriers with incomplete penetrance. Bioinformatics programs (PolyPhen-2, SIFT, and MutationTaster) predicted the mutation to be deleterious. The lysine at the mutation position was highly conserved from Drosophila to humans and was recognized as a methylation location in the GATA4 protein. The involvement of the lysine methylation in cardiogenesis by attenuating the transcriptional activity of GATA4 in mice has been previously examined. Our study broadens the mutation spectrum of the GATA4 gene and reveals for the first time a mutation at the methylation position of GATA4 associated with ASD.
    Full-text · Article · Sep 2015 · Gene
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    • "Congenital heart disease (CHD) accounts for 25% of all birth defects and is a leading cause of death in children b 1 year of age [1]. Nearly 80% of all CHD cases are idiopathic and multiple lines of evidence indicate a genetic contribution to CHD, but only relatively limited progress has been made in identifying the genetic basis of CHD [2] [3]. Conotruncal defects, such as tetralogy of Fallot (TOF), result from disruption in the flow of tissue-specific information between the first and second heart fields at approximately 20 days of gestation. "

    Full-text · Dataset · Jul 2015
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    • "CHD represent a diverse group of structural and functional abnormalities of the heart that occur during early embryogenesis. With an incidence of nearly 1%, CHD pose a serious global health concern and cause significant financial and social burden (Waitzman et al. 1994; van Rijen et al. 2005; Russo and Elixhauser 2007) which remains in spite of major advances made to improve diagnoses and treatment (Fahed et al. 2013). "
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    ABSTRACT: The goal of this study was to identify the contribution of common genetic variants to Down syndrome-associated atrioventricular septal defect, a severe heart abnormality. Compared to the euploid population, infants with Down syndrome, or trisomy 21, have a 2000-fold increased risk of presenting with atrioventricular septal defects. The cause of this elevated risk remains elusive. Here we present data from the largest heart study conducted to date on a trisomic background using a carefully characterized collection of individuals from extreme ends of the phenotypic spectrum. We performed a genome-wide association study using logistic regression analysis on 452 individuals with Down syndrome, consisting of 210 cases with complete atrioventricular septal defects and 242 controls with structurally normal hearts. No individual variant achieved genome-wide significance. We identified four disomic regions (1p36.3, 5p15.31, 8q22.3, and 17q22) and two trisomic regions on chromosome 21 (around PDXK and KCNJ6 genes) that merit further investigation in large replication studies. Our data show that a few common genetic variants of large effect size (odds ratio > 2.0) do not account for the elevated risk of Down syndrome-associated atrioventricular septal defects. Instead, multiple variants of low-to-moderate effect sizes may contribute to this elevated risk, highlighting the complex genetic architecture of atrioventricular septal defects even in the highly susceptible Down syndrome population. Copyright © 2015 Author et al.
    Full-text · Article · Jul 2015 · G3-Genes Genomes Genetics
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