Submission Details

The WAC gene encodes a multi-functional protein that plays a role in coupling H2B monoubiquitination with transcription elongation, starvation-induced autophagy, golgi biogenesis, functional augmin complex, and regulation of energy-mediated mTORC1 activity. Additionally, it is highly expressed in the postnatal brain. WAC was first reported in relation to autosomal dominant Desanto-Shinawi syndrome in 2015 (DeSanto et al., PMID:26264232). This disorder is characterized by a spectrum of neurodevelopmental phenotypes including speech and language difficulties, motor delays, intellectual disability, behavioral issues and seizures, as well as extra-neurological features including growth delay, heart defects, hearing loss, and kidney abnormalities. Additionally, this disorder is associated with distinctive facial features including prominent forehead, deep-set eyes, depressed nasal bridge, bulbous nasal dip, and bushy eyebrows. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Desanto-Shinawi syndrome (MONDO:0018760): WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome and facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to WAC point mutation. Six variants (including frameshift and nonsense) that have been reported in six probands in three publications (PMIDs: 25356899, 26264232, 26757981) are included in this curation. More evidence is available in the literature (PMIDs: 23033978, 29663678, 29928181, 32214004, 33123400, 33387902, 34997803, 34797027, 35636632, 35018708), but the maximum score for genetic evidence (12 pts.) has been reached. The vast majority of reported variants are de novo, with five variants reported to be due to confirmed or suspected parental germline mosaicisim. There are several recurrent variants that have been reported in more than one unrelated patient including: c.374C>A, p.(Ser125*); c.381+4_381+7delAGTA, p.(Gly92Alafs2); c.1648C>T, p.(Arg550); c.1661_1664del, p.(Ser554*). The mechanism of pathogenicity is known to be heterozygous loss-of-function (LOF). This gene-disease relationship is also supported by drosophila model studies (PMID: 26757981) which demonstrated that RNAi induced knockdown of WAC expression caused an altered behavioral phenotype in a drosophila light-off jump reflex habituation test. Additionally, there is a preprint manuscript available at bioRxiv (https://doi.org/10.1101/2022.01.24.477600) in which a constitutive mouse Wac model has been generated and capitulates many of the phenotypes observed in humans. In summary, there is definitive evidence to support the relationship between WAC and autosomal dominant Desanto-Shinawi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability/Autism expert panel on 11/10/2022 (SOP Version 9).