Here we summarise our current understanding of ZIC3 function and describe the potential role ZIC3 plays in important signalling pathways and their links to heterotaxy.
A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene.
Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy.
We sought to develop a hypomorphic Zic3 mouse to model human heterotaxy and investigate developmental mechanisms underlying variability in cardiac phenotypes.
Patients with TGA (n = 169), double outlet right ventricle (DORV; n = 89), common atrioventricular canal (CAVC; n = 41), and heterotaxy (n = 54) underwent sequencing of ZIC3 exons.
These results define the temporal and spatial requirements for Zic3 in node morphogenesis, left-right patterning and cardiac development and suggest the possibility that a requirement for Zic3 in node ultrastructure underlies its role in heterotaxy and laterality disorders.
Longitudinal follow-up revealed that this family has X-linked heterotaxy due to a missense mutation, c.1048A>G(R350G), in the third zinc finger domain of ZIC3.
The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation.
Previously we mapped a locus for situs abnormalities in humans, HTX1, to Xq26.2 by linkage analysis in a single family (LR1) and by detection of a deletion in an unrelated situs ambiguus male (Family LR2; refs 2,3).
Previously we mapped a locus for situs abnormalities in humans, HTX1, to Xq26.2 by linkage analysis in a single family (LR1) and by detection of a deletion in an unrelated situs ambiguus male (Family LR2; refs 2,3).