CFC1 mutations in patients with transposition of the great arteries and double-outlet right ventricle

Abstract

Recent investigations identified heterozygous CFC1 mutations in subjects with heterotaxy syndrome, all of whom had congenital cardiac malformations, including malposition of the great arteries. We hypothesized that a subset of patients with similar types of congenital heart disease---namely, transposition of the great arteries and double-outlet right ventricle, in the absence of laterality defects---would also have CFC1 mutations. Our analysis of the CFC1 gene in patients with these cardiac disorders identified two disease-related mutations in 86 patients. The present study identifies the first autosomal single-gene defect for these cardiac malformations and indicates that some cases of transposition of the great arteries and double-outlet right ventricle can share a common genetic etiology with heterotaxy syndrome. In addition, these results demonstrate that the molecular pathway involving CFC1 plays a critical role in normal and abnormal cardiovascular development.

Figure 1

Diagrams of the normal heart (A), D-TGA (B), and DORV (C). In the normal heart, the pulmonary artery arises from the right ventricle, and the aorta arises from the left ventricle. In D-TGA, the great arteries have been switched. In DORV, the aorta and pulmonary artery both arise from the right ventricle. Both D-TGA and DORV can display additional anatomic variations. RA = right atrium; LA = left atrium; LA = left ventricle; RV = right ventricle; AO = aorta; PA = pulmonary artery.

Figure 2

Splice-site duplication in a patient with TGA. A, Tandem 20-bp duplication (red) of the exon 4 splice-donor site found in a subject with TGA. The native and duplicated splice sites are indicated by an arrow (↓). The star marks where the duplication occurred. Both the wild-type and the mutant sequence are demonstrated. B, Wild-type and mutant gene structure demonstrates signal peptide sequence (SS; turquoise), conserved EGF-like domain (EGF; red), conserved-CFC domain (CFC; green), hydrophobic domain (HD; dark blue), and predicted altered sequence in mutant protein (light blue). The conserved CFC domain and hydrophobic region are not present in the predicted product.