WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

Janson J. White, Juliana F. Mazzeu, Zeynep Coban-Akdemir, Yavuz Bayram, Vahid Bahrambeigi, Alexander Hoischen, Bregje W. M. van Bon, Alper Gezdirici, Elif Yilmaz Gulec, Francis Ramond, Renaud Touraine, Julien Thevenon, Marwan Shinawi, Erin Beaver, Jennifer Heeley, Julie Hoover-Fong, Ceren D. Durmaz, Halil Gurhan Karabulut, Ebru Marzioglu-Ozdemir, Atilla CayirMehmet B. Duz, Mehmet Seven, Susan Price, Barbara Merfort Ferreira, Angela M. Vianna-Morgante, Sian Ellard, Andrew Parrish, Karen Stals, Josue Flores-Daboub, Shalini N. Jhangiani, Richard A. Gibbs, Han G. Brunner, V. Reid Sutton, James R. Lupski, Claudia M. B. Carvalho*, Baylor-Hopkins Ctr Mendelian

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, similar to 70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered-1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.
Original languageEnglish
Pages (from-to)27-43
Number of pages17
JournalAmerican Journal of Human Genetics
Volume102
Issue number1
DOIs
Publication statusPublished - 4 Jan 2018

Keywords

  • NEURAL-TUBE DEFECTS
  • DROSOPHILA TISSUE POLARITY
  • AUTOSOMAL-DOMINANT
  • CELL POLARITY
  • VERTEBRATE GASTRULATION
  • MENDELIAN-INHERITANCE
  • GROWTH-PLATE
  • DEP DOMAIN
  • MUTATIONS
  • PROTEIN

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