Congenital heart disease: emerging themes linking genetics and development

Abstract

Although congenital heart disease (CHD) is the most common survivable birth defect, the etiology of most CHD remains unclear. Several lines of evidence from humans and vertebrate models have supported a genetic component for CHD, yet the extreme locus heterogeneity and lack of a distinct genotype-phenotype correlation have limited causative gene discovery. However, recent advances in genomic technologies are permitting detailed evaluation of the genetic abnormalities in large cohorts of CHD patients. This has led to the identification of copy-number variation and de novo mutations together accounting for up to 15% of CHD. Further, new strategies coupling human genetics with model organisms have provided mechanistic insights into the molecular and developmental pathways underlying CHD pathogenesis, notably chromatin remodeling and ciliary signaling.

Figure 1

The clinical spectrum of congenital heart disease (CHD). CHD is associated with a continuous range of extracardiac phenotypes, extending from the chromosomal aneuploidies manifesting with multiple organ system involvement (left side of figure) through combinations of CHD and one other involved organ system such as Holt-Oram Syndrome and Primary Ciliary Dyskinesia to apparently isolated CHD (right side of figure).

Figure 2

Cilia structure and ciliary components associated with CHD. (A, B) The ciliary compartment is defined by the axoneme (Ax), transition (TZ) and basal body (BB). The axoneme consists of 9 microtubule doublets arranged in a circle, which provide a cytoskeletal scaffold for the cilium, and surrounded by the ciliary membrane. The basal body serves to anchor, stabilize and regulate the formation of the cilium. The transition zone is positioned between the axoneme and basal body and serves as a docking site for ciliary trafficking. PM: plasma membrane. (B) Numerous ciliary components from the Ax, TZ and BB have been linked to CHD in both humans and model organisms. (C) Transmission electron microscopy (TEM) image of a transverse cross-section through the axoneme of a motile cilium from the skin epithelia of a Xenopus embryo. Orange arrowhead indicates the microtubule doublet ring structure. Scalebar, 100 nm. (D) Scanning electron microscopy (SEM) image of a motile cilium on the left-right organizer (LRO) of a Xenopus embryo. Scalebar, 2 µm (E) SEM image of multi-ciliated cells on the skin epithelia of a Xenopus embryo. Scalebar, 10 µm

Figure 3

Chromatin remodeling genes in CHD. Nucleosome with histone octamer, H3K4 methylation and H2BK120 ubiquitination is shown. Genes associated with identified syndromes with CHD are shown in red, genes associated with identified syndromes without known CHD are shown in blue, genes with de-novo mutation in CHD patients are underlined.