Article

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: 11.09). 02/2013; 112(4):707-20. DOI: 10.1161/CIRCRESAHA.112.300853
Source: PubMed

ABSTRACT 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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    • "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. "
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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.
    G3-Genes Genomes Genetics 07/2015; DOI:10.1534/g3.115.019943 · 2.51 Impact Factor
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    • "Congenital heart disease (CHD) accounts for 25% of all birth defects and is a leading cause of death in children <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 field at approximately 20 days of gestation. "
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    ABSTRACT: Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several genes that regulate heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and MBNL2). In addition, we used antisense morpholinos to knock down the expression of two scaRNAs (scarna1 and snord94) in zebrafish and saw a corresponding disruption of heart development with an accompanying alteration in splice isoforms of cardiac regulatory genes. Based on these combined results, we hypothesize that scaRNA modification of spliceosomal RNAs assists in fine tuning the spliceosome for dynamic selection of mRNA splice isoforms. Our results are consistent with disruption of splicing patterns during early embryonic development leading to insufficient communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for determining the mechanisms underlying congenital cardiac malformations. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 04/2015; 9(8). DOI:10.1016/j.bbadis.2015.04.016 · 5.09 Impact Factor
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