title: Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.
abstract: 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 disorders. 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.
authors.affiliation: Department of Genome Sciences and The Howard Hughes Medical Institute, University of Washington School of Medicine, 1705 NE Pacific St., Seattle, Washington 98195, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sharp
authors.forename: Sierra
authors.initials: S
authors.lastname: Hansen
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Selzer
authors.forename: Ze
authors.initials: Z
authors.lastname: Cheng
authors.forename: Regina
authors.initials: R
authors.lastname: Regan
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.forename: Sue M
authors.initials: SM
authors.lastname: Price
authors.forename: Edward
authors.initials: E
authors.lastname: Blair
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Fitzpatrick
authors.forename: Rick
authors.initials: R
authors.lastname: Segraves
authors.forename: Todd A
authors.initials: TA
authors.lastname: Richmond
authors.forename: Cheryl
authors.initials: C
authors.lastname: Guiver
authors.forename: Donna G
authors.initials: DG
authors.lastname: Albertson
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinkel
authors.forename: Peggy S
authors.initials: PS
authors.lastname: Eis
authors.forename: Stuart
authors.initials: S
authors.lastname: Schwartz
authors.forename: Samantha J L
authors.initials: SJ
authors.lastname: Knight
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D019457:Chromosome Breakage; D002872:Chromosome Deletion; D022202:Chromosomes, Artificial, Bacterial; D002886:Chromosomes, Human, Pair 17; D018628:Gene Dosage; D020440:Gene Duplication; D015321:Gene Rearrangement; D015894:Genome, Human; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics*; D009030:Mosaicism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020161:Physical Chromosome Mapping; D011110:Polymorphism, Genetic