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Title: De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila
Authors: Lugtenberg, Dorien ×
Reijnders, Margot R F
Fenckova, Michaela
Bijlsma, Emilia K
Bernier, Raphael
van Bon, Bregje W M
Smeets, Eric
Vulto-van Silfhout, Anneke T
Bosch, Danielle
Eichler, Evan E
Mefford, Heather C
Carvill, Gemma L
Bongers, Ernie M H F
Schuurs-Hoeijmakers, Janneke Hm
Ruivenkamp, Claudia A
Santen, Gijs W E
van den Maagdenberg, Arn M J M
Peeters-Scholte, Cacha M P C D
Kuenen, Sabine
Verstreken, Patrik
Pfundt, Rolph
Yntema, Helger G
de Vries, Petra F
Veltman, Joris A
Hoischen, Alexander
Gilissen, Christian
de Vries, Bert B A
Schenck, Annette
Kleefstra, Tjitske
Vissers, Lisenka E L M #
Issue Date: Aug-2016
Publisher: Nature Publishing Group
Series Title: European Journal of Human Genetics vol:24 issue:8
Article number: 10.1038/ejhg.2015.282
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.European Journal of Human Genetics advance online publication, 13 January 2016; doi:10.1038/ejhg.2015.282.
URI: 
ISSN: 1018-4813
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Neuronal Communication
× corresponding author
# (joint) last author

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