Clinical and molecular delineation of the 17q21.31 microdeletion syndrome (original) (raw)
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
- 1
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands - 2
Department of Genome Sciences, University of Washington School of Medicine, Seattle, USA - 3
Department of Genetic Medicine and Development, University of Geneva Medical School CMU, Geneva, Switzerland - 4
Department of Clinical Genetics, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Oxford, UK - 5
Department of Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK - 6
Oxford Genetics Knowledge Park, The Wellcome Trust Centre for Human Genetics, Churchill Hospital, Oxford, UK - 7
Department of Genetics, Rouen University Hospital, & Inserm U614, Institute for Biomedical research, University of Rouen, Rouen, France - 8
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium - 9
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium - 10
Antwerp University Hospital, Antwerp, Belgium - 11
Hunter Genetics, Hunter New England Area Health Service, Newcastle, NSW, Australia - 12
Genetic Services, McMaster University Medical Centre, Hamilton, Canada - 13
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada - 14
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands - 15
JC Self Research Institute, Greenwood Genetic Center, Greenwood, USA - 16
Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy - 17
Fondazione IRCCS Policlinico San Matteo, Pavia, Italy - 18
Genome Sequencing Center, Washington University School of Medicine, St. Louis, MO, USA - 19
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany - 20
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA - 21
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA - 22
Institute of Human Genetics, GSF National Research Center for Environment and Health, Munich-Neuherberg, Germany - 23
Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brasil - 24
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK - 25
Howard 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
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.
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Journal of Medical Genetics 2009; 46 576-576 Published Online First: 31 Jul 2009. doi: 10.1136/jmg.2008.058701corr1