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Clinical and molecular delineation of the 17q21.31 microdeletion syndrome
  1. D A Koolen1,
  2. A J Sharp2,3,
  3. J A Hurst4,
  4. H V Firth5,
  5. S J L Knight6,
  6. A Goldenberg7,
  7. P Saugier-Veber7,
  8. R Pfundt1,
  9. L E L M Vissers1,
  10. A Destrée8,
  11. B Grisart8,
  12. L Rooms9,
  13. N Van der Aa10,
  14. M Field11,
  15. A Hackett11,
  16. K Bell12,
  17. M J M Nowaczyk13,
  18. G M S Mancini14,
  19. P J Poddighe14,
  20. C E Schwartz15,
  21. E Rossi16,
  22. M De Gregori16,
  23. L L Antonacci-Fulton18,
  24. M D McLellan II18,
  25. J M Garrett18,
  26. M A Wiechert18,
  27. T L Miner18,
  28. S Crosby18,
  29. R Ciccone16,
  30. L Willatt5,
  31. A Rauch19,
  32. M Zenker19,
  33. S Aradhya20,
  34. M A Manning21,
  35. T M Strom22,
  36. J Wagenstaller22,
  37. A C Krepischi-Santos23,
  38. A M Vianna-Morgante23,
  39. C Rosenberg23,
  40. S M Price4,
  41. H Stewart4,
  42. C Shaw-Smith5,
  43. H G Brunner1,
  44. A O M Wilkie24,
  45. J A Veltman1,
  46. O Zuffardi16,17,
  47. E E Eichler2,25,
  48. B B A de Vries1
  1. 1
    Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  2. 2
    Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA
  3. 3
    Department of Genetic Medicine and Development, University of Geneva Medical School CMU, Geneva, Switzerland
  4. 4
    Department of Clinical Genetics, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Oxford, UK
  5. 5
    Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK
  6. 6
    Oxford Genetics Knowledge Park, The Wellcome Trust Centre for Human Genetics, Churchill Hospital, Oxford, UK
  7. 7
    Department of Genetics, Rouen University Hospital, & Inserm U614, Institute for Biomedical research, University of Rouen, Rouen, France
  8. 8
    Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium
  9. 9
    Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
  10. 10
    Antwerp University Hospital, Antwerp, Belgium
  11. 11
    Hunter Genetics, Hunter New England Area Health Service, Newcastle, NSW, Australia
  12. 12
    Genetic Services, McMaster University Medical Centre, Hamilton, Canada
  13. 13
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  14. 14
    Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  15. 15
    JC Self Research Institute, Greenwood Genetic Center, Greenwood, USA
  16. 16
    Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
  17. 17
    Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
  18. 18
    Genome Sequencing Center, Washington University School of Medicine, St. Louis, MO, USA
  19. 19
    Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  20. 20
    Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
  21. 21
    Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
  22. 22
    Institute of Human Genetics, GSF National Research Center for Environment and Health, Munich-Neuherberg, Germany
  23. 23
    Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brasil
  24. 24
    Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
  25. 25
    Howard Hughes Medical Institute, Seattle, USA
  1. Dr B B A de Vries, Department of Human Genetics 849, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; B.deVries{at}


Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.

Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.

Results: We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10−5).

Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

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  • Competing interests: None.

  • Funding: This work was supported by grants from the AnEUploidy project (LSHG-CT-2006-037627) supported by the European commission under FP6, and supplemental grants from the Netherlands Organisation for Health Research and Development (ZonMW 907-00-058, ZonMW 917-86-319 to BBAdV, ZonMW 920-03-338 to DAK, ZonMW 912-04-047 to HGB and JAV), Hersenstichting Nederland (BBAdV), South Carolina Department of Disabilities and Special Needs (CES) and the National Institutes of Health (NIH) (EEE, HD043569). EEE is an Investigator of the Howard Hughes Medical Institute.

  • Patient consent: Parental consent obtained

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