WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.

2.50
Hdl Handle:
http://hdl.handle.net/11287/620589
Title:
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.
Authors:
White, J. J. [et al]; Ellard, Sian ( 0000-0002-7620-5526 ) ; Stals, Karen
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.
Citation:
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. 2017 Am. J. Hum. Genet.
Publisher:
Elsevier
Journal:
American journal of human genetics
Issue Date:
16-Dec-2017
URI:
http://hdl.handle.net/11287/620589
DOI:
10.1016/j.ajhg.2017.10.002
PubMed ID:
29276006
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0002929717304226
Type:
Journal Article
Language:
en
ISSN:
1537-6605
Appears in Collections:
Molecular Genetics; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWhite, J. J. [et al]en
dc.contributor.authorEllard, Sianen
dc.contributor.authorStals, Karenen
dc.date.accessioned2017-12-29T11:43:04Z-
dc.date.available2017-12-29T11:43:04Z-
dc.date.issued2017-12-16-
dc.identifier.citationWNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. 2017 Am. J. Hum. Genet.en
dc.identifier.issn1537-6605-
dc.identifier.pmid29276006-
dc.identifier.doi10.1016/j.ajhg.2017.10.002-
dc.identifier.urihttp://hdl.handle.net/11287/620589-
dc.description.abstractLocus 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.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0002929717304226en
dc.rightsArchived with thanks to American journal of human geneticsen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleWNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of human geneticsen
dc.type.versionIn press (epub ahead of print)en

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