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 ... 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 genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).
Zlotogora et al. (1987) described a family in which 4 out of 7 children had situs inversus and/or congenital heart disease; more specifically, 3 had situs inversus with a normal heart in one and 3 had heart defects ... Zlotogora et al. (1987) described a family in which 4 out of 7 children had situs inversus and/or congenital heart disease; more specifically, 3 had situs inversus with a normal heart in one and 3 had heart defects with normal organ orientation in one.
In a family in which several members had situs ambiguus shown to be due to mutation in the ZIC3 gene (300265), Gebbia et al. (1997) found a normal male with a daughter with situs ambiguus; neither the father ... In a family in which several members had situs ambiguus shown to be due to mutation in the ZIC3 gene (300265), Gebbia et al. (1997) found a normal male with a daughter with situs ambiguus; neither the father nor the daughter carried any mutation in the coding region of ZIC3 and both parents were anatomically normal. Paternity was confirmed, the mother was unrelated to the rest of the family, and the daughter had a 46,XX karyotype. Because observations in mice had suggested that heterozygous mutations in human NODAL may be associated with human situs abnormalities, Gebbia et al. (1997) searched for mutations in the NODAL gene. In the affected daughter and her unaffected mother, they found an arg183-to-gln substitution (R183Q; 601265.0001) in the prodomain of NODAL. None of more than 200 control chromosomes carried this substitution, and no other NODAL mutations were identified in other members of that family or in any other individual harboring a mutant ZIC3 allele. In 14 of 269 patients with either classic heterotaxy or looping cardiovascular malformations (CVM), Mohapatra et al. (2009) identified 4 different missense variants (see, e.g., 601265.0002), 1 in-frame insertion/deletion (601265.0003), and 2 conserved splice site variants (see, e.g., 601265.0004) in the NODAL gene. Although similar with regard to other associated defects, individuals with the NODAL mutations had a significantly higher occurrence of pulmonary valve atresia (p = 0.001) compared with individuals without a detectable NODAL mutation. Functional analysis demonstrated that the missense variant forms of NODAL exhibited significant impairment of signaling as measured by decreased Cripto (TDGF1; 187395) coreceptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of SMAD2 phosphorylation and impaired SMAD2 nuclear import. Mohapatra et al. (2009) proposed a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human left-right patterning defects.