Submission Details

The WDFY3 gene encodes a large multidomain scaffolding protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. A WDFY3 missense variant in the PH domain of the protein was reported in 2016 in a large family with autosomal dominant microcephaly and mild to moderate intellectual disability (Kadir et al., PMID: 27008544). Since then, several mostly de novo variants in WDFY3 have been reported, including nonsense, frameshift, splice, and missense variants. Affected individuals present with developmental delay, intellectual disability, autism spectrum disorder, hypotonia, seizures, and abnormal head size, either microcephaly or macrocephaly (PMIDs: 27824329, 28263302, 30564305, 31130284, 31327001). It has been suggested that WDFY3 haploinsufficiency leads to macrocephaly or large-normal head size, while missense variants in the PH domain of WDFY3 cause microcephaly (two such variants reported) through opposing effects on the Wnt pathway (PMID: 31327001). Although this hypothesis appears to be supported by a transgenic fly model overexpressing a human WDFY3 mutant (PMID: 27008544) and several Wdfy3 loss-of-function mouse models (PMID: 25198012, 27648578, 31327001), further evidence is needed to clarify the effect of WDFY3 variants on head size and the mechanisms involved.

In summary, there is definitive evidence supporting the relationship between WDFY3 and autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 19, 2022 (SOP Version 8).

Data provided by the ClinGen Prenatal GCEP from April 8, 2025 secondary analysis:

There is no clear evidence for prenatal phenotypes in WDFY3-syndromic intellectual disability at the time of this curation. The only reported prenatal phenotype is hypoplastic left heart found in a fetus with a de novo WDFY3 frameshift variant (PMID: 33898534). No cases with fetal hydrops have been reported.