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A detailed clinical analysis of 13 patients with AUTS2 syndrome further delineates the phenotypic spectrum and underscores the behavioural phenotype
  1. Gea Beunders1,
  2. Jiddeke van de Kamp1,
  3. Pradeep Vasudevan2,
  4. Jenny Morton3,
  5. Katrien Smets4,5,6,
  6. Tjitske Kleefstra7,
  7. Sonja A de Munnik7,
  8. Janneke Schuurs-Hoeijmakers7,
  9. Berten Ceulemans8,
  10. Marcella Zollino9,
  11. Sabine Hoffjan10,
  12. Stefan Wieczorek10,
  13. Joyce So11,12,13,
  14. Leanne Mercer11,
  15. Tanya Walker11,
  16. Lea Velsher11,14,
  17. the DDD study15,
  18. Michael J Parker16,
  19. Alex C Magee17,
  20. Bart Elffers18,
  21. R Frank Kooy19,
  22. Helger G Yntema7,
  23. Elizabeth J Meijers-Heijboer1,
  24. Erik A Sistermans1
  1. 1Department of Clinical Genetics, VU University Medical Center Amsterdam, The Netherlands
  2. 2Department of Clinical Genetics, University Hospitals of Leicester, Leicester, UK
  3. 3Department of Clinical Genetics, Birmingham Women's Hospital, Edgbaston, Birmingham, UK
  4. 4Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
  5. 5Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium
  6. 6Laboratories of Neurogenetics and Neuropathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  7. 7Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
  8. 8Department of Neurology- Paediatric Neurology, University and University Hospital Antwerp, Antwerp, Belgium
  9. 9Institute of Medical Genetics, ‘A. Gemelli’ School of Medicine, Catholic University Rome, Italy
  10. 10Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany
  11. 11Northwestern Ontario Regional Genetics Program, Thunder Bay District Health Unit, Thunder Bay, Canada
  12. 12The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, Canada
  13. 13Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
  14. 14Genetics Program, North York General Hospital, Toronto, Canada
  15. 15Wellcome Trust Sanger Institute, Cambridge, UK
  16. 16Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK
  17. 17Genetic Medicine, Belfast City Hospital, Belfast, UK
  18. 18Department of Medical Care for Patients with Intellectual Disability, AMSTA, Amsterdam, The Netherlands
  19. 19Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium
  1. Correspondence to G Beunders, Department of Clinical Genetics, VU University Medical Center Amsterdam, Reception D, De Boellelaan 1117, Amsterdam 1081 HV, The Netherlands; g.beunders{at}vumc.nl

Abstract

Background AUTS2 syndrome is an ‘intellectual disability (ID) syndrome’ caused by genomic rearrangements, deletions, intragenic duplications or mutations disrupting AUTS2. So far, 50 patients with AUTS2 syndrome have been described, but clinical data are limited and almost all cases involved young children.

Methods We present a detailed clinical description of 13 patients (including six adults) with AUTS2 syndrome who have a pathogenic mutation or deletion in AUTS2. All patients were systematically evaluated by the same clinical geneticist.

Results All patients have borderline to severe ID/developmental delay, 83–100% have microcephaly and feeding difficulties. Congenital malformations are rare, but mild heart defects, contractures and genital malformations do occur. There are no major health issues in the adults; the oldest of whom is now 59 years of age. Behaviour is marked by it is a friendly outgoing social interaction. Specific features of autism (like obsessive behaviour) are seen frequently (83%), but classical autism was not diagnosed in any. A mild clinical phenotype is associated with a small in-frame 5′ deletions, which are often inherited. Deletions and other mutations causing haploinsufficiency of the full-length AUTS2 transcript give a more severe phenotype and occur de novo.

Conclusions The 13 patients with AUTS2 syndrome with unique pathogenic deletions scattered around the AUTS2 locus confirm a phenotype–genotype correlation. Despite individual variations, AUTS2 syndrome emerges as a specific ID syndrome with microcephaly, feeding difficulties, dysmorphic features and a specific behavioural phenotype.

  • Genetics
  • Developmental
  • Clinical genetics
  • Copy-number
  • Psychiatry

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