Koolen David A, Pfundt Rolph, de Leeuw Nicole, Hehir-Kwa Jayne Y, Nillesen Willy M, Neefs Ineke, Scheltinga Ine, Sistermans Erik, Smeets Dominique, Brunner Han G, van Kessel Ad Geurts, Veltman Joris A, de Vries Bert B A
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hum Mutat. 2009 Mar;30(3):283-92. doi: 10.1002/humu.20883.
Microarray-based copy number analysis has found its way into routine clinical practice, predominantly for the diagnosis of patients with unexplained mental retardation. However, the clinical interpretation of submicroscopic copy number variants (CNVs) is complicated by the fact that many CNVs are also present in the general population. Here we introduce and discuss a workflow that can be used in routine diagnostics to assess the clinical significance of the CNVs identified. We applied this scheme to our cohort of 386 individuals with unexplained mental retardation tested using a genome-wide tiling-resolution DNA microarray and to 978 additional patients with mental retardation reported in 15 genome-wide microarray studies extracted from the literature. In our cohort of 386 patients we identified 25 clinically significant copy number losses (median size 2.6 Mb), nine copy number gains (median size 2.0 Mb), and one mosaic numerical chromosome aberration. Accordingly, the overall diagnostic yield of clinically significant CNVs was 9.1%. Taken together, our cohort and the patients described in the literature include a total of 1,364 analyses of DNA copy number in which a total of 11.2% (71.9% losses, 19.6% gains, 8.5% complex) could be identified, reflecting the overall diagnostic yield of clinically significant CNVs in individuals with unexplained mental retardation.
基于微阵列的拷贝数分析已进入常规临床实践，主要用于诊断不明原因智力迟钝的患者。然而，亚微观拷贝数变异（CNV）的临床解释较为复杂，因为许多CNV在普通人群中也存在。在此，我们介绍并讨论一种可用于常规诊断的工作流程，以评估所识别的CNV的临床意义。我们将此方案应用于我们的386例不明原因智力迟钝个体队列，这些个体使用全基因组平铺分辨率DNA微阵列进行检测，并应用于从文献中提取的15项全基因组微阵列研究报告的另外978例智力迟钝患者。在我们的386例患者队列中，我们识别出25个具有临床意义的拷贝数缺失（中位大小2.6 Mb）、9个拷贝数增加（中位大小2.0 Mb）和1个嵌合性染色体数目畸变。因此，具有临床意义的CNV的总体诊断率为9.1%。综合来看，我们的队列以及文献中描述的患者总共进行了1364次DNA拷贝数分析，其中总共可识别出11.2%（缺失占71.9%，增加占19.6%，复杂情况占8.5%），这反映了不明原因智力迟钝个体中具有临床意义的CNV的总体诊断率。
