ArticleAmerican journal of human genetics2018
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
Article in American journal of human genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 111 citations in OpenAlex.
- Robinow syndrome DVL1 variants disrupt morphogenesis and appendage formation in a Drosophila disease model.Developmental dynamics : an official publication of the American Association of Anatomists · 2026Article
- Clarifying Frizzled 2 function in development through genetically validated mouse models.Disease models & mechanisms · 2026Article
- The abnormal C-terminus caused by DVL1 variants impacts Robinow syndrome phenotypes.Human molecular genetics · 2026Article
- Article
- Distinct sub-clusters of developmental disorder-associated variants in the switch II region of RAC1.European journal of human genetics : EJHG · 2026Article
- Multi-Level Genomic and Computational Analyses Identify a Novel IFT122 Variant Associated With Cranioectodermal Dysplasia 1 in a Consanguineous Saudi Family.Molecular genetics & genomic medicine · 2026Article
- Proposed differential diagnosis and classification of non-syndromic and syndromic supernumerary teeth.BMC oral health · 2026Article
- Wnt5a Regulates Embryonic Müllerian Duct Development Through the Non-Canonical Wnt PCP Pathway.Cells · 2026Article
- Local Misalignment Scoring Reveals Spatially Uniform Chondrocyte Disorganization in a Wnt5a-C83S Knock-in Model of Robinow Syndrome.Research square · 2025Article
- Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation.Human molecular genetics · 2025Article
- ATranslational pediatrics · 2025Article
- Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation.bioRxiv : the preprint server for biology · 2025Article
- Clinical and Molecular Cytogenetic Characterization of 2 Sibling Cases with 17q25 Duplication due to Unbalanced Translocation.Molecular syndromology · 2024Article
- Molecules That Have Rarely Been Studied in Lymphatic Endothelial Cells.International journal of molecular sciences · 2024Review
- The origin and evolution of Wnt signalling.Nature reviews. Genetics · 2024Review
- Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome.Disease models & mechanisms · 2024Article
- Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.eLife · 2024Article
- An unusual presentation of de novo RAC3 variation in prenatal diagnosis.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2024Article
- Core planar cell polarity genesProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Closing the gap: Solving complex medically relevant genes at scale.medRxiv : the preprint server for health sciences · 2024Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
36 authors at 18 institutions in 6 countries.
Funding
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, ∼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.
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