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The Molecular Causes of Robinow Syndrome

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The molecular causes of Robinow Syndrome

Locus heterogeneity characterizes a variety of skeletal dysplasias due to interacting or overlapping
signaling pathways. Robinow syndrome is a distinctive skeletal dysplasia which remained without a
gene association for more than 30 years. Discovery of pathogenic variants ROR2, in autosomal
recessive families and WNT5A variants in a few autosomal dominant Robinow (DRS) cases
revealed that the noncanonical Wnt pathway is perturbed in Robinow syndrome. Recently, we
applied whole exome sequencing (WES) and discovered that -1 frameshifting affecting the Cterminus
of the encoded dishevelled proteins, DVL1 or DVL3, cause ~20% of DRS. DVL is a
conserved key mediator of the Wnt pathway and serves as a signaling hub for diverse cellular
pathways. We hypothesize that other relevant genes in the Wnt pathway may underlie the remaining
DRS cases. To address this, we recruited 31 individuals with Robinow or Robinow-like phenotypes
to be studied in collaboration with the Baylor-Hopkins Center for Mendelian Genomics. Preliminary
analyses confirmed that indels affecting the C-terminal region of DVL1/DVL3 contribute to ~20% of
cases. Remarkably, 29% of the subjects carry variants in genes known to cause diseases that are
considered within the differential diagnoses of DRS such as FGD1 in Aarskog-Scott syndrome.
Additionally, variants in FZD2, recently associated with Omodysplasia, contributes to 13% of the
cases. Importantly, FZD2 is a relevant protein partner in the WNT5A interactome, supporting its role
in skeletal development. In summary, our study illuminates the molecular causes of this rare
Mendelian disorder, and reveal the contribution of distinct genes from the same pathway to help
explain locus heterogeneity in Robinow Syndrome.

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