Relevance to Autism

Two de novo LoF variants in the WDFY3 gene (both nonsense) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant was identifed in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016, while a fourth de novo LoF variant was observed in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. Mice carrying deleterious alleles of the Wdfy3 gene exhibit a regionally enlarged cerebral cortex, which resembles the early brain outgrowth observed in many autistic children, as well as migration defects of cortical projection neurons (PMID 25198012). Transmission and de novo association (TADA) analysis of ASD cases and controls from the Autism Sequencing Consortium and the Simons Simplex Collection in Sanders et al., 2015 identified WDFY3 as an ASD candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified WDFY3 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a phosphatidylinositol 3-phosphate-binding protein that functions as a master conductor for aggregate clearance by autophagy. This protein shuttles from the nuclear membrane to colocalize with aggregated proteins, where it complexes with other autophagic components to achieve macroautophagy-mediated clearance of these aggregated proteins. However, it is not necessary for starvation-induced macroautophagy.

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Model Summary

Homozygous disconnected mice display perinatal lethality, and neurodevelopmental anomalies.

References