Relevance to Autism

Two de novo LoF variants in the WAC gene (both frameshift) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). A third de novo LoF variant in the WAC gene was recently identified in an ASD proband in PMID 26325558. 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 WAC as an ASD candidate gene with a false discovery rate (FDR) 0.01; a FDR 0.01 was replicated for this gene following TADA analysis in Satterstrom et al., 2020. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PMID 26264232 identified de novo LoF variants in WAC in patients with developmental delay. PMID 26757981 reported additional ID cases with de novo, potentially gene disruptive WAC variants; two of these cases also presented with autism. Clinical evalution of patients from PMIDs 26264232 and 26757981 revealed phenotypic overlap consisting of developmental delay/intellectual disability, hypotonia, behavioral problems, and distinctive facial dysmorphism, possibly defining a novel form of syndromic intellectual disability. Similar clinical features have been reported in individuals with 10p12-p11 microdeletion syndrome, for which the shortest deleted region contains the WAC gene (Wentzel et al., 2011; Okamoto et al., 2012). 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 WAC as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

Acts as a linker between gene transcription and histone H2B monoubiquitination at 'Lys-120' (H2BK120ub1). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription. Regulates the cell-cycle checkpoint activation in response to DNA damage. Positive regulator of amino acid starvation-induced autophagy. May negatively regulate the ubiquitin proteasome pathway.

External Links

References