title: 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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.affiliation: 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.
authors.forename: Margot R F
authors.initials: MR
authors.lastname: Reijnders
authors.affiliation: 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.
authors.forename: Michaela
authors.initials: M
authors.lastname: Fenckova
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: Department of Clinical Genetics, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Smeets
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Bosch
authors.affiliation: Department Genome Sciences, University of Washington, Seattle, WA, USA.|Howard Hughes Medical Institute, Seattle, WA, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, USA.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Janneke Hm
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Ruivenkamp
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Gijs W E
authors.initials: GW
authors.lastname: Santen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cacha M P C D
authors.initials: CM
authors.lastname: Peeters-Scholte
authors.affiliation: VIB, Center for the Biology of Disease, Leuven, Belgium.|KU Leuven, Center for Human Genetics, Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuenen
authors.affiliation: VIB, Center for the Biology of Disease, Leuven, Belgium.|KU Leuven, Center for Human Genetics, Leuven Institute for Neuroscience and Disease (LIND), Leuven, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Petra F
authors.initials: PF
authors.lastname: de Vries
authors.affiliation: 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, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: 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.
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
authors.affiliation: 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.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: 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.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000175:diagnosis / Q000235:genetics*; D004330:Drosophila / Q000235:genetics / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006185:Habituation, Psychophysiologic; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007858:Learning; D007859:Learning Disabilities / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D013577:Syndrome; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D029721:Drosophila Proteins; C539695:WAC protein, Drosophila; C574643:WAC protein, human