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Review
. 2013 Feb 15;112(4):707-20.
doi: 10.1161/CIRCRESAHA.112.300853.

Genetics of Congenital Heart Disease: The Glass Half Empty

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Free PMC article
Review

Genetics of Congenital Heart Disease: The Glass Half Empty

Akl C Fahed et al. Circ Res. .
Free PMC article

Erratum in

  • Circ Res. 2013 Jun 7;112(12):e182

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.

Figures

Figure 1
Figure 1
Locations of heart malformations that are usually identified in infancy, and estimated prevalence based upon the CONCOR database{van der Bom, 2012 #1149}. Numbers indicate the birth prevalence per million live births. Abbreviations: CoA, Coarctation of the Aorta; AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; Ebstein, Ebstein anomaly; HLH, hypoplastic left heart; MA, mitral atresia; PDA, patent ductus arteriosus, PS, pulmonary stenosis; PTA, persistent truncus arteriosus; TA, tricuspid atresia; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect; SV, Single Ventricle.
Figure 2
Figure 2
Strategies to define the genetic architecture of CHD are illustrated by experimental platforms, approaches, and expected deliverables. Boxes that extend across categories indicate that multiple strategies can provide comparable data.

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