WDFY3 – Autism Spectrum Disorder

Heterozygous de novo likely gene-disruptive variants in WDFY3 have been identified in multiple unrelated ASD probands. In a Chinese cohort of 1,045 ASD trios, recurrent de novo LGD mutations in WDFY3 were observed in ≥2 unrelated probands, ranking among the top recurrent genes in ASD (PMID:27824329).

An independent series of 13 individuals with de novo WDFY3 variants—nine protein-truncating and four missense—presented overlapping neurodevelopmental phenotypes including intellectual disability and ASD in several subjects (PMID:31327001).

WDFY3-related ASD follows a predominantly autosomal dominant, de novo inheritance mode with a variant spectrum encompassing nonsense, frameshift, splice-site, and missense changes. A representative pathogenic variant is c.217A>T (p.Lys73Ter). No evidence of transmission or segregation in multiplex families has been reported.

In vivo mouse models demonstrate that Wdfy3 haploinsufficiency disrupts neuronal migration, leading to focal laminar mispositioning of cortical projection neurons, altered dendritic arborization, and synaptic morphology—phenotypes analogous to ASD pathology (PMID:35733184).

Mechanistic studies reveal that WDFY3 functions as an autophagy scaffold regulating Wnt signaling; loss-of-function perturbations impair aggregate clearance and dysregulate Wnt-dependent neurogenesis, aligning with observed human phenotypes (PMID:31327001).

Collectively, the accumulation of de novo WDFY3 variants across independent cohorts, coupled with concordant functional models, supports a strong gene–disease relationship. Screening for WDFY3 variants informs ASD diagnosis and encourages targeted investigation into autophagy and Wnt signaling in neurodevelopment.

References

• Nature communications • 2016 • De novo genic mutations among a Chinese autism spectrum disorder cohort. PMID:27824329
• Brain : a journal of neurology • 2019 • Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size. PMID:31327001
• Molecular autism • 2022 • WDFY3 mutation alters laminar position and morphology of cortical neurons. PMID:35733184

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