De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

Abstract

Recently WAC was reported as a candidate gene for intellectual disability (ID) based on the identification of a de novo mutation in an individual with severe ID. WAC regulates transcription-coupled histone H2B ubiquitination and has previously been implicated in the 10p12p11 contiguous gene deletion syndrome. In this study, we report on 10 individuals with de novo WAC mutations which we identified through routine (diagnostic) exome sequencing and targeted resequencing of WAC in 2326 individuals with unexplained ID. All but one mutation was expected to lead to a loss-of-function of WAC. Clinical evaluation of all individuals revealed phenotypic overlap for mild ID, hypotonia, behavioral problems and distinctive facial dysmorphisms, including a square-shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. These clinical features were also previously reported in individuals with 10p12p11 microdeletion syndrome. To investigate the role of WAC in ID, we studied the importance of the Drosophila WAC orthologue (CG8949) in habituation, a non-associative learning paradigm. Neuronal knockdown of Drosophila CG8949 resulted in impaired learning, suggesting that WAC is required in neurons for normal cognitive performance. In conclusion, we defined a clinically recognizable ID syndrome, caused by de novo loss-of-function mutations in WAC. Independent functional evidence in Drosophila further supported the role of WAC in ID. On the basis of our data WAC can be added to the list of ID genes with a role in transcription regulation through histone modification.

Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

“…All seven variants were detected by the initial WGS experiments but not recognized as pathogenic. At the time of the first data annotation in 2014, five of the seven genes (AP3B2, HMGA2, KCNB1, SON, and WAC) were not recognized in OMIM to cause human disease [17][18][19][20][21][22]. In one case (SMAD6), the phenotypes of the individuals reported in the literature did not overlap the clinical presentation of our patient.…”

DeSanto-Shinawi Syndrome: First Case in South America

“…WAC encodes a protein that plays an essential role in multiple cell processes, including transcription, microtubule development, autophagy, and regulation of the Golgi apparatus function [Joachim et al, 2012;Lugtenberg et al, 2016]. Furthermore, it regulates histone transcription and ubiquitination by mediating the interaction between E3 ligase and RNF20-RNF40, thereby inhibiting chromatin organization and gene transcription [Totsukawa et al, 2011].…”

Conservation of the behavioral and transcriptional response to social experience among Drosophilids

“…Interestingly, the autism-linked Wac gene, which has been shown to affect nonassociative conditioning in D. melanogaster, was also significantly upregulated in D. erecta relative to the rest of the melanogaster subgroup (Table S2). 54 Genes involved in chemoreception and processing in the peripheral nervous system (PNS), like Cyp6a20, are generally thought to be under strong selection during behavioral evolution. [55][56][57] The PNSexpressed odorant-binding protein (Obp) genes, which specifically shuttle odorants and pheromones to odorant receptor neurons, 58 were also enriched among differentially expressed transcripts in D. erecta (P = 0.007).…”