Nature Genetics
- 38, 1038 - 1042 (2006)
Published online: 13 August 2006; | doi:10.1038/ng1862
Discovery of previously unidentified genomic disorders from the duplication architecture of the human genomeAndrew J Sharp1, Sierra Hansen1, Rebecca R Selzer2, Ze Cheng1, Regina Regan3, Jane A Hurst4, Helen Stewart4, Sue M Price4, Edward Blair4, Raoul C Hennekam5, 6, Carrie A Fitzpatrick7, Rick Segraves8, Todd A Richmond2, Cheryl Guiver3, Donna G Albertson8, 9, Daniel Pinkel8, Peggy S Eis2, Stuart Schwartz7, Samantha J L Knight3 & Evan E Eichler11
Department of Genome Sciences and The Howard Hughes Medical Institute, University of Washington School of Medicine, 1705 NE Pacific St., Seattle, Washington 98195, USA. 2
NimbleGen Systems, Inc., Madison, Wisconsin 53711, USA. 3
Oxford Genetics Knowledge Park, The Wellcome Trust Centre for Human Genetics, Churchill Hospital, Oxford OX3 7BN, UK. 4
Department of Clinical Genetics, Oxford Radcliffe Hospitals National Health Service (NHS) Trust, Churchill Hospital, Oxford OX3 7LJ, UK. 5
Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, London, UK. 6
Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. 7
Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA. 8
Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, California 94143, USA. 9
Cancer Research Institute, UCSF, San Francisco, California 94143, USA.
Correspondence should be addressed to Evan E Eichler eee@gs.washington.edu Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders1. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.
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