title: GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila.
abstract: BACKGROUND
  GATA zinc finger domain containing 2B (GATAD2B) encodes a subunit of the MeCP1-Mi-2/nucleosome remodelling and deacetylase complex involved in chromatin modification and regulation of transcription. We recently identified two de novo loss-of-function mutations in GATAD2B by whole exome sequencing in two unrelated individuals with severe intellectual disability.
  
  
  METHODS
  To identify additional individuals with GATAD2B aberrations, we searched for microdeletions overlapping with GATAD2B in inhouse and international databases, and performed targeted Sanger sequencing of the GATAD2B locus in a selected cohort of 80 individuals based on an overlap with the clinical features in the two index cases. To address whether GATAD2B is required directly in neurones for cognition and neuronal development, we investigated the role of Drosophila GATAD2B orthologue simjang (simj) in learning and synaptic connectivity.
  
  
  RESULTS
  We identified a third individual with a 240 kb microdeletion encompassing GATAD2B and a fourth unrelated individual with GATAD2B loss-of-function mutation. Detailed clinical description showed that all four individuals with a GATAD2B aberration had a distinctive phenotype with childhood hypotonia, severe intellectual disability, limited speech, tubular shaped nose with broad nasal tip, short philtrum, sparse hair and strabismus. Neuronal knockdown of Drosophila GATAD2B orthologue, simj, resulted in impaired learning and altered synapse morphology.
  
  
  CONCLUSIONS
  We hereby define a novel clinically recognisable intellectual disability syndrome caused by loss-of-function of GATAD2B. Our results in Drosophila suggest that GATAD2B is required directly in neurones for normal cognitive performance and synapse development.
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Marjolein H
authors: MH
authors: Willemsen
authors: Bonnie
authors: B
authors: Nijhof
authors: Michaela
authors: M
authors: Fenckova
authors: Willy M
authors: WM
authors: Nillesen
authors: Ernie M H F
authors: EM
authors: Bongers
authors: Anna
authors: A
authors: Castells-Nobau
authors: Lenke
authors: L
authors: Asztalos
authors: Erika
authors: E
authors: Viragh
authors: Bregje W M
authors: BW
authors: van Bon
authors: Emre
authors: E
authors: Tezel
authors: Joris A
authors: JA
authors: Veltman
authors: Han G
authors: HG
authors: Brunner
authors: Bert B A
authors: BB
authors: de Vries
authors: Joep
authors: J
authors: de Ligt
authors: Helger G
authors: HG
authors: Yntema
authors: Hans
authors: H
authors: van Bokhoven
authors: Bertrand
authors: B
authors: Isidor
authors: Cédric
authors: C
authors: Le Caignec
authors: Elsa
authors: E
authors: Lorino
authors: Zoltan
authors: Z
authors: Asztalos
authors: David A
authors: DA
authors: Koolen
authors: Lisenka E L M
authors: LE
authors: Vissers
authors: Annette
authors: A
authors: Schenck
authors: Tjitske
authors: T
authors: Kleefstra
mesh_terms: D000818:Animals; D001483:Base Sequence; D002648:Child; D002872:Chromosome Deletion; D056915:DNA Copy Number Variations; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D050980:GATA Transcription Factors / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D007859:Learning Disabilities / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D012097:Repressor Proteins; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome
chemical_list: D050980:GATA Transcription Factors; C468770:GATAD2B protein, human; D012097:Repressor Proteins
keywords: GATAD2B; chromatin modification; intellectual disability syndrome