Functional analysis of germline VANGL2 variants using rescue assays of vangl2 knockout zebrafish

Christopher J. Derrick, Emmanuelle Szenker-Ravi, Adrian Santos-Ledo, Ahlam Alqahtani, Amirah Yusof, Lorraine Eley, Alistair H.L. Coleman, Sumanty Tohari, Alvin Yu Jin Ng, Byrappa Venkatesh, Essa Alharby, Luke Mansard, Marie Noelle Bonnet-Dupeyron, Anne Francoise Roux, Christel Vaché, Joëlle Roume, Patrice Bouvagnet, Naif A.M. Almontashiri, Deborah J. Henderson, Bruno Reversade*Bill Chaudhry*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), nonsyndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.

Original languageEnglish (US)
Pages (from-to)150-169
Number of pages20
JournalHuman Molecular Genetics
Issue number2
StatePublished - Jan 15 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press.


  • congenital heart defect
  • neural tube defect
  • planar cell polarity
  • variant of unknown significance
  • zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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