Contract grant sponsors: National Institutes of Health (RO1 HL088639, HL088639-03S1); Burroughs Wellcome Clinical Scientist Awards in Translational Research (#1008496).
Genetic and Functional Analyses of ZIC3 Variants in Congenital Heart Disease
Article first published online: 14 NOV 2013
© 2013 WILEY PERIODICALS, INC.
Volume 35, Issue 1, pages 66–75, January 2014
How to Cite
Cowan, J., Tariq, M. and Ware, S. M. (2014), Genetic and Functional Analyses of ZIC3 Variants in Congenital Heart Disease. Hum. Mutat., 35: 66–75. doi: 10.1002/humu.22457
Communicated by Sergio Ottolenghi
- Issue published online: 18 DEC 2013
- Article first published online: 14 NOV 2013
- Accepted manuscript online: 7 OCT 2013 10:47AM EST
- Manuscript Accepted: 23 SEP 2013
- Manuscript Received: 29 APR 2013
- National Institutes of Health. Grant Numbers: RO1 HL088639, HL088639-03S1
- Burroughs Wellcome Clinical Scientist Awards in Translational Research. Grant Number: #1008496
- left-right patterning;
- congenital heart disease
Mutations in zinc-finger in cerebellum 3 (ZIC3) result in heterotaxy or isolated congenital heart disease (CHD). The majority of reported mutations cluster in zinc-finger domains. We previously demonstrated that many of these lead to aberrant ZIC3 subcellular trafficking. A relative paucity of N- and C-terminal mutations has, however, prevented similar analyses in these regions. Notably, an N-terminal polyalanine expansion was recently identified in a patient with VACTERL, suggesting a potentially distinct function for this domain. Here we report ZIC3 sequencing results from 440 unrelated patients with heterotaxy and CHD, the largest cohort yet examined. Variants were identified in 5.2% of sporadic male cases. This rate exceeds previous estimates of 1% and has important clinical implications for genetic testing and risk-based counseling. Eight of 11 were novel, including 5 N-terminal variants. Subsequent functional analyses included four additional reported but untested variants. Aberrant cytoplasmic localization and decreased luciferase transactivation were observed for all zinc-finger variants, but not for downstream or in-frame upstream variants, including both analyzed polyalanine expansions. Collectively, these results expand the ZIC3 mutational spectrum, support a higher than expected prevalence in sporadic cases, and suggest alternative functions for terminal mutations, highlighting a need for further study of these domains.