Genetic and Functional Analyses of ZIC3 Variants in Congenital Heart Disease

Jason Cowan, Muhammad Tariq, Stephanie M. Ware

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)66-75
Number of pages10
JournalHuman Mutation
Volume35
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • Congenital heart disease
  • Heterotaxy
  • Left-right patterning
  • Symmetry
  • ZIC3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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