Simon-Sanchez Javier, Scholz Sonja, Matarin Maria del Mar, Fung Hon-Chung, Hernandez Dena, Gibbs J Raphael, Britton Angela, Hardy John, Singleton Andrew
Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland 20892, USA.
Hum Mutat. 2008 Feb;29(2):315-22. doi: 10.1002/humu.20626.
Technologies that allow genotyping of more than 100,000 polymorphisms in a single assay enable the execution of genomewide SNP (GWSNP) association studies to identify common genetic variants underlying traits. Less appreciated is the ability of GWSNP assays to map and directly identify rare mutations that cause disease. Here we show the use of this approach in identifying rare structural mutations involved in disease using a large cohort of Parkinson disease (PD) patients and neurologically normal controls by examination of genotype data and copy number metrics. This approach revealed a patient with homozygous mutation at the PARK2 locus. In addition, two heterozygous deletion mutations and five heterozygous duplication mutations within PARK2 were identified in PD subjects and controls. All mutations were confirmed by independent gene dosage experiments. These data demonstrate the utility of this approach in the direct detection of mutations that underlie disease.
能够在一次检测中对超过10万个多态性进行基因分型的技术，使得全基因组单核苷酸多态性（GWSNP）关联研究得以开展，以识别性状背后的常见遗传变异。GWSNP检测用于定位和直接识别导致疾病的罕见突变的能力却较少受到关注。在此，我们展示了这种方法在使用大量帕金森病（PD）患者和神经功能正常对照人群，通过检查基因型数据和拷贝数指标来识别与疾病相关的罕见结构突变中的应用。这种方法揭示了一名在PARK2位点存在纯合突变的患者。此外，在PD受试者和对照中还鉴定出了PARK2内的两个杂合缺失突变和五个杂合重复突变。所有突变均通过独立的基因剂量实验得到证实。这些数据证明了这种方法在直接检测疾病潜在突变方面的实用性。
