Clinical and molecular delineation of the 17q21.31 microdeletion syndrome
- D A Koolen1,
- A J Sharp2,3,
- J A Hurst4,
- H V Firth5,
- S J L Knight6,
- A Goldenberg7,
- P Saugier-Veber7,
- R Pfundt1,
- L E L M Vissers1,
- A Destrée8,
- B Grisart8,
- L Rooms9,
- N Van der Aa10,
- M Field11,
- A Hackett11,
- K Bell12,
- M J M Nowaczyk13,
- G M S Mancini14,
- P J Poddighe14,
- C E Schwartz15,
- E Rossi16,
- M De Gregori16,
- L L Antonacci-Fulton18,
- M D McLellan II18,
- J M Garrett18,
- M A Wiechert18,
- T L Miner18,
- S Crosby18,
- R Ciccone16,
- L Willatt5,
- A Rauch19,
- M Zenker19,
- S Aradhya20,
- M A Manning21,
- T M Strom22,
- J Wagenstaller22,
- A C Krepischi-Santos23,
- A M Vianna-Morgante23,
- C Rosenberg23,
- S M Price4,
- H Stewart4,
- C Shaw-Smith5,
- H G Brunner1,
- A O M Wilkie24,
- J A Veltman1,
- O Zuffardi16,17,
- E E Eichler2,25,
- B B A de Vries1
- 1Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- 2Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA
- 3Department of Genetic Medicine and Development, University of Geneva Medical School CMU, Geneva, Switzerland
- 4Department of Clinical Genetics, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Oxford, UK
- 5Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK
- 6Oxford Genetics Knowledge Park, The Wellcome Trust Centre for Human Genetics, Churchill Hospital, Oxford, UK
- 7Department of Genetics, Rouen University Hospital, & Inserm U614, Institute for Biomedical research, University of Rouen, Rouen, France
- 8Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium
- 9Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
- 10Antwerp University Hospital, Antwerp, Belgium
- 11Hunter Genetics, Hunter New England Area Health Service, Newcastle, NSW, Australia
- 12Genetic Services, McMaster University Medical Centre, Hamilton, Canada
- 13Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- 14Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
- 15JC Self Research Institute, Greenwood Genetic Center, Greenwood, USA
- 16Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy
- 17Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- 18Genome Sequencing Center, Washington University School of Medicine, St. Louis, MO, USA
- 19Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
- 20Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
- 21Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
- 22Institute of Human Genetics, GSF National Research Center for Environment and Health, Munich-Neuherberg, Germany
- 23Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brasil
- 24Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
- 25Howard Hughes Medical Institute, Seattle, USA
- 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}antrg.umcn.nl
- Received 11 March 2008
- Revised 21 May 2008
- Accepted 29 May 2008
- Published Online First 15 July 2008
Abstract
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.
Footnotes
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Competing interests: None.
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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.
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Patient consent: Parental consent obtained
