WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome - Université de Bourgogne Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2018

WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome

Alexander Hoischen
  • Fonction : Auteur
Bregje W.M. van Bon
  • Fonction : Auteur
Alper Gezdirici
  • Fonction : Auteur
Elif Yilmaz Gulec
  • Fonction : Auteur
Francis Ramond
  • Fonction : Auteur
  • PersonId : 843752
Renaud Touraine
  • Fonction : Auteur
Marwan Shinawi
  • Fonction : Auteur
Erin Beaver
  • Fonction : Auteur
Jennifer Heeley
  • Fonction : Auteur
Julie Hoover-Fong
  • Fonction : Auteur
Ceren D. Durmaz
  • Fonction : Auteur
Halil Gurhan Karabulut
  • Fonction : Auteur
Ebru Marzioglu-Ozdemir
  • Fonction : Auteur
Atilla Cayir
  • Fonction : Auteur
Mehmet B. Duz
  • Fonction : Auteur
Mehmet Seven
  • Fonction : Auteur
Susan Price
  • Fonction : Auteur
Barbara Merfort Ferreira
  • Fonction : Auteur
Angela M. Vianna-Morgante
  • Fonction : Auteur
Sian Ellard
  • Fonction : Auteur
  • PersonId : 886467
Andrew Parrish
  • Fonction : Auteur
Karen Stals
  • Fonction : Auteur
  • PersonId : 886464
Josue Flores-Daboub
  • Fonction : Auteur
Shalini N. Jhangiani
  • Fonction : Auteur
Richard Gibbs
  • Fonction : Auteur
  • PersonId : 946258

Résumé

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, ∼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.

Dates et versions

hal-01727782 , version 1 (09-03-2018)

Identifiants

Citer

Janson J. White, Juliana F. Mazzeu, Zeynep Coban-Akdemir, Yavuz Bayram, Vahid Bahrambeigi, et al.. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. American Journal of Human Genetics, 2018, 102 (1), pp.27 - 43. ⟨10.1016/j.ajhg.2017.10.002⟩. ⟨hal-01727782⟩
42 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More