Mutation in ZIC3 (OMIM #306955), a zinc finger transcription factor, causes heterotaxy (situs ambiguus) or isolated congenital heart defects in humans. Mice bearing a null mutation in Zic3 have left-right patterning defects with associated cardiovascular, vertebra/rib, and central nervous system malformations. Although XZic3 is thought to play a critical role in Xenopus neural crest development, no defects in tissues derived from neural crest are apparent in adult Zic3^null mice. In this study we have characterized the effect of a PGK-neo cassette insertion 5' of the Zic3 locus. The Zic3 transcript in this new allele is up-regulated in ES cells and in E9.0 embryos, but no ectopic expression was detected. Unlike the Zic3^null mutation in which only 20% of mutant animals survive to adulthood, there was no evidence of excess fetal death caused by the Zic3^neo allele. Zic3^neo mutant mice exhibited hemifacial microsomia, asymmetric low set ears, axial skeletal defects, kyphosis and scoliosis; a combination of defects which mimics Goldenhar Syndrome. Some Zic3^neo mice had evidence of left-right axis patterning defects, but cardiac malformation was much less common than in the Zic3^null mutants. A six-week old hemizygous mouse was found to have thoraco-cervical ectopia cordis, an extremely rare congenital malformation in humans and for which there is no precedent in a mouse model.