Heterotaxy, Visceral, 2, Autosomal

A number sign (#) is used with this entry because of evidence that visceral heterotaxy-2 (HTX2) is caused by heterozygous mutation in the CFC1 gene (605194) on chromosome 2q21.

Description

Heterotaxy ('heter' meaning 'other' and 'taxy' meaning 'arrangement'), or situs ambiguus, is a developmental condition characterized by randomization of the placement of visceral organs, including the heart, lungs, liver, spleen, and stomach. The organs are oriented randomly with respect to the left-right axis and with respect to one another (Srivastava, 1997). Heterotaxy is a clinically and genetically heterogeneous disorder.

For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Clinical Features

Bamford et al. (2000) reported 3 unrelated patients with laterality defects. One patient had complex cardiac anomalies, right-sided stomach, and intestinal malrotation. This patient also had microcephaly, absent corpus callosum, and myelocele. The second patient had dextrocardia, transposition of the great arteries (TGA), L-isomerism of the lungs, transverse liver, polysplenia, and intestinal malrotation. The third patient had dextrocardia, TGA, R-isomerism of the lungs, bilateral superior vena cava, right-sided stomach, and asplenia.

Isolated Cardiac Anomalies

Transposition of the great arteries (TGA) and double-outlet right ventricle (DORV) account for 5% and 2%, respectively, of all congenital heart disease (Perry et al., 1993). Goldmuntz et al. (2002) noted that cardiac laterality defects, including dextro-looped TGA (DTGA) and DORV, are a characteristic finding in visceral or thoracic heterotaxy syndromes, although they are most frequently seen in isolation. In addition, some patients in families with laterality defects may have isolated congenital heart defects without additional laterality defects. Since CFC1 mutations had been identified in patients with heterotaxy syndrome, all of whom had congenital cardiac malformations, Goldmuntz et al. (2002) analyzed the CFC1 gene in 86 patients with these cardiac disorders and found that 2 had heterozygous pathogenic mutations (605194.0002 and 605194.0004). One patient had DTGA with an intact ventricular septum and pyloric stenosis, whereas the other had DORV with a subpulmonic ventricular septal defect and aortic arch hypoplasia.

Mapping

Autosomal visceral heterotaxy-2 is caused by mutation in the CFC1 gene (605194), which maps to chromosome 2 (Bamford et al., 2000).

Molecular Genetics

In 3 unrelated patients with variable visceral heterotaxic phenotypes, Bamford et al. (2000) identified 2 different heterozygous loss-of-function mutations in the CFC1 gene (605194.0001 and 605194.0002). The mutant proteins had aberrant cellular localization in transfected cells and were functionally defective in a zebrafish 'one-eyed pinhead' (oep)-mutant rescue assay. The findings indicated that the essential role of EGF-CFC genes and Nodal signaling in left-right axis formation is conserved from fish to humans. Moreover, the results supported a role for environmental and/or genetic modifiers in determining the ultimate phenotype in humans.