Hoyer Juliane, Dreweke Alexander, Becker Christian, Göhring Ina, Thiel Christian T, Peippo Maarit M, Rauch Ralf, Hofbeck Michael, Trautmann Udo, Zweier Christiane, Zenker Martin, Hüffmeier Ulrike, Kraus Cornelia, Ekici Arif B, Rüschendorf Franz, Nürnberg Peter, Reis André, Rauch Anita
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany.
J Med Genet. 2007 Oct;44(10):629-36. doi: 10.1136/jmg.2007.050914. Epub 2007 Jun 29.
Using array techniques, it was recently shown that about 10% of patients with mental retardation of unknown origin harbour cryptic chromosomal aneusomies. However, data analysis is currently not standardised and little is known about its sensitivity and specificity.
We have developed an electronic data analysis tool for gene-mapping SNP arrays, a software tool that we call Copy Number Variation Finder (CNVF). Using CNVF, we analysed 104 unselected patients with mental retardation of unknown origin with a genechip mapping 100K SNP array and established an optimised set of analysis parameters.
We detected deletions as small as 20 kb when covered by at least three single-nucleotide polymorphisms (SNPs) and duplications as small as 150 kb when covered by at least six SNPs, with only one false-positive signal in six patients. In 9.1% of patients, we detected apparently disease-causing or de novo aberrations ranging in size from 0.4 to 14 Mb. Morphological anomalies in patients with de novo aberrations were equal to that of unselected patients when measured with de Vries score.
Our standardised CNVF data analysis tool is easy to use and has high sensitivity and specificity. As some genomic regions are covered more densely than others, the genome-wide resolution of the 100K array is about 400-500 kb for deletions and 900-1000 kb for duplications. The detection rate of about 10% of de novo aberrations is independent of selection of patients for particular features. The incidental finding in two patients of heterozygosity for the 250 kb recurrent deletion at the NPH1 locus, associated with autosomal recessive juvenile nephronophthisis, which was inherited from a healthy parent, highlights the fact that inherited aberrations might be disease-related even though not causal for mental retardation.
最近利用阵列技术显示，约10%病因不明的智力迟钝患者存在隐匿性染色体非整倍体。然而，目前数据分析尚未标准化，对其敏感性和特异性了解甚少。
我们开发了一种用于基因定位SNP阵列的电子数据分析工具，一种我们称为拷贝数变异查找器（CNVF）的软件工具。使用CNVF，我们用一张可定位10万个SNP的基因芯片分析了104例未经过挑选的病因不明的智力迟钝患者，并建立了一套优化的分析参数。
当至少被三个单核苷酸多态性（SNP）覆盖时，我们检测到小至20 kb的缺失；当至少被六个SNP覆盖时，检测到小至150 kb的重复，六名患者中只有一个假阳性信号。在9.1%的患者中，我们检测到明显的致病或新生畸变，大小从0.4到14 Mb不等。用德弗里斯评分法测量时，新生畸变患者的形态异常与未经过挑选的患者相同。
我们的标准化CNVF数据分析工具易于使用，具有高敏感性和特异性。由于某些基因组区域的覆盖密度高于其他区域，10万阵列的全基因组分辨率对于缺失约为400 - 500 kb，对于重复约为900 - 1000 kb。约10%的新生畸变检测率与根据特定特征挑选患者无关。在两名患者中偶然发现了与常染色体隐性青少年肾单位肾痨相关的NPH1位点250 kb反复缺失的杂合性，该缺失是从健康父母遗传而来的，这突出了一个事实，即遗传畸变即使不是智力迟钝的病因，也可能与疾病相关。
