Submission Details

The WNT5A gene is located on chromosome 3 at 3p14.3 and encodes the Wnt family member 5A protein, which is a ligand for members of the frizzled family of seven transmembrane receptors, and is involved in both the canonical and noncanonical signaling pathways, depending upon the receptor context. WNT proteins play an essential role during development, controlling processes such as embryonic patterning, cell growth, migration, and differentiation. The WNT5A gene was first reported in relation to autosomal dominant Robinow syndrome in 2010 (Person et al., PMID 19918918). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands from four publications (Person et al., 2010 PMID 19918918; Roifman et al., 2015 PMID 24716670; Xiong et al., 2016 PMID 27092434; White et al., 2018 PMID 29276006). Variants in this gene segregate with disease in approximately nine family members from three families. As a result of this re-evaluation, five additional variants in six probands (one duplication and four missense variants) reported in four publications (PMIDs: 34627339. 35047859, 35586607, 34750320) have been included in this curation. The mechanism of disease has not been clearly defined, but missense variants were most commonly reported, with functional data for two of the missense variants suggesting they are hypomorphic (Person et al., 2010 PMID 19918918). Of note, there is one report of an autosomal recessive form of Robinow syndrome caused by a homozygous frameshift variant in WNT5A, resulting in perinatal death (Birgmeier et al., 2018 PMID 29575632). This gene-disease relationship is supported by expression data, biochemical function data, a knockout mouse model and a chick embryo limb model expressing a WNT5A variant found in a proband (Yamaguchi et al., 1999 PMID 10021340; Oishi et al., 2003 PMID 12839624; Mikels and Nusse, 2006 PMID 16602827; Gignac et al., 2019 PMID 31032853). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on October 27th, 2020 (SOP Version 8). This GDR was re-evaluated on April 25th, 2024 (SOP Version 10). Although new genetic evidence was published (PMIDs: 34627339. 35047859, 35586607, 34750320), the classification did not change.