Situs inversus totalis and a novel ZIC3 mutation in a family with X-linked heterotaxy.

Disorders of laterality consist of a complex set of malformations resulting from failure to establish normal asymmetry along the left-right axis, and include both heterotaxy and situs inversus totalis. Zinc fingers in cerebellum 3 (ZIC3) was the first gene to be definitively associated with heterotaxy syndromes in humans (OMIM #306955), with 13 mutations previously described in both familial and sporadic cases. We now report the clinical and molecular characterization of a five-generation family originally reported in 1974 as having X-linked dextrocardia. 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 pedigree demonstrates the first reported case of situs inversus totalis associated with a ZIC3 mutation in a male and the second reported case of incomplete penetrance in an unaffected transmitting male, as well as a wide range of phenotypes of varying severity. Several affected members also exhibit renal and hindgut malformations, consistent with previously reported secondary features in ZIC3 mutations. The spectrum of features in this family emphasizes the importance of thorough molecular and imaging studies in both sporadic and familial cases of heterotaxy to ensure accurate prenatal diagnosis and recurrence risk counseling.