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Original Article
GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila
  1. Marjolein H Willemsen1,
  2. Bonnie Nijhof1,2,3,
  3. Michaela Fenckova1,2,3,
  4. Willy M Nillesen1,
  5. Ernie M H F Bongers1,
  6. Anna Castells-Nobau1,2,3,
  7. Lenke Asztalos4,
  8. Erika Viragh5,
  9. Bregje W M van Bon1,
  10. Emre Tezel1,2,3,
  11. Joris A Veltman1,2,6,
  12. Han G Brunner1,6,
  13. Bert B A de Vries1,6,
  14. Joep de Ligt1,2,6,
  15. Helger G Yntema1,
  16. Hans van Bokhoven1,2,3,
  17. Bertrand Isidor7,
  18. Cédric Le Caignec7,
  19. Elsa Lorino8,
  20. Zoltan Asztalos4,5,9,
  21. David A Koolen1,
  22. Lisenka E L M Vissers1,2,6,
  23. Annette Schenck1,2,3,
  24. Tjitske Kleefstra1,3,6
  1. 1Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
  2. 2Nijmegen Center for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
  3. 3Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Genetics, Aktogen, University of Cambridge, Cambrigde, UK
  5. 5Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
  6. 6Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands
  7. 7Service de Génétique Médicale, CHU Nantes, Nantes, France
  8. 8Service de Pédiatrie, CHU Nantes, Nantes, France
  9. 9Aktogen Hungary Ltd., Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary
  1. Correspondence to Dr Tjitske Kleefstra and Dr Annette Schenck, Department of Human Genetics, Radboud University Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands; t.kleefstra{at}gen.umcn.nl; a.schenck{at}gen.umcn.nl

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.

  • GATAD2B
  • intellectual disability syndrome
  • chromatin modification

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