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Eur J Hum Genet. 2016 Aug;24(8):1145-53. doi: 10.1038/ejhg.2015.282. Epub 2016 Jan 13.

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

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Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Psychiatry, University of Washington, Seattle, WA, USA.
Department of Clinical Genetics, University of Maastricht, Maastricht, The Netherlands.
Department Genome Sciences, University of Washington, Seattle, WA, USA.
Howard Hughes Medical Institute, Seattle, WA, USA.
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
VIB, Center for the Biology of Disease, Leuven, Belgium.
KU Leuven, Center for Human Genetics, Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.


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.

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