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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.

SUBMITTER: Lugtenberg D 

PROVIDER: S-EPMC4970694 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Lugtenberg Dorien D   Reijnders Margot R F MR   Fenckova Michaela M   Bijlsma Emilia K EK   Bernier Raphael R   van Bon Bregje W M BW   Smeets Eric E   Vulto-van Silfhout Anneke T AT   Bosch Danielle D   Eichler Evan E EE   Mefford Heather C HC   Carvill Gemma L GL   Bongers Ernie M H F EM   Schuurs-Hoeijmakers Janneke Hm JH   Ruivenkamp Claudia A CA   Santen Gijs W E GW   van den Maagdenberg Arn M J M AM   Peeters-Scholte Cacha M P C D CM   Kuenen Sabine S   Verstreken Patrik P   Pfundt Rolph R   Yntema Helger G HG   de Vries Petra F PF   Veltman Joris A JA   Hoischen Alexander A   Gilissen Christian C   de Vries Bert B A BB   Schenck Annette A   Kleefstra Tjitske T   Vissers Lisenka E L M LE  

European journal of human genetics : EJHG 20160113 8

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  ...[more]

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