Sharp Andrew J, Hansen Sierra, Selzer Rebecca R, Cheng Ze, Regan Regina, Hurst Jane A, Stewart Helen, Price Sue M, Blair Edward, Hennekam Raoul C, Fitzpatrick Carrie A, Segraves Rick, Richmond Todd A, Guiver Cheryl, Albertson Donna G, Pinkel Daniel, Eis Peggy S, Schwartz Stuart, Knight Samantha J L, Eichler Evan E
Department of Genome Sciences and The Howard Hughes Medical Institute, University of Washington School of Medicine, 1705 NE Pacific St., Seattle, Washington 98195, USA.
Nat Genet. 2006 Sep;38(9):1038-42. doi: 10.1038/ng1862. Epub 2006 Aug 13.
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.
基因组疾病的特征是存在侧翼节段性重复序列，这些重复序列使这些区域易于发生反复重排。基于基因组的重复结构，我们研究了130个区域，我们假设这些区域是先前未描述的基因组疾病的候选区域。我们通过BAC阵列比较基因组杂交对290名智力发育迟缓个体进行了检测，鉴定出16种致病性重排，包括在4名个体中发现的17q21.31的新生微缺失。使用寡核苷酸阵列，我们细化了这种微缺失的断点，确定了一个478 kb的关键区域，该区域包含在所有4名个体中均被删除的6个基因。我们将这种缺失以及1q21.1、15q13、15q24和17q12中其他4种致病性重排的断点定位到侧翼节段性重复序列，表明这些也是反复重排的位点。与17q21.31缺失一样，这些断点区域是对照中拷贝数多态性的位点，表明这些可能是本质上不稳定的基因组区域。
