Veltman Joris A, Schoenmakers Eric F P M, Eussen Bert H, Janssen Irene, Merkx Gerard, van Cleef Brigitte, van Ravenswaaij Conny M, Brunner Han G, Smeets Dominique, van Kessel Ad Geurts
Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Am J Hum Genet. 2002 May;70(5):1269-76. doi: 10.1086/340426. Epub 2002 Apr 9.
Telomeric chromosome rearrangements may cause mental retardation, congenital anomalies, and miscarriages. Automated detection of subtle deletions or duplications involving telomeres is essential for high-throughput diagnosis, but impossible when conventional cytogenetic methods are used. Array-based comparative genomic hybridization (CGH) allows high-resolution screening of copy number abnormalities by hybridizing differentially labeled test and reference genomes to arrays of robotically spotted clones. To assess the applicability of this technique in the diagnosis of (sub)telomeric imbalances, we here describe a blinded study, in which DNA from 20 patients with known cytogenetic abnormalities involving one or more telomeres was hybridized to an array containing a validated set of human-chromosome-specific (sub)telomere probes. Single-copy-number gains and losses were accurately detected on these arrays, and an excellent concordance between the original cytogenetic diagnosis and the array-based CGH diagnosis was obtained by use of a single hybridization. In addition to the previously identified cytogenetic changes, array-based CGH revealed additional telomere rearrangements in 3 of the 20 patients studied. The robustness and simplicity of this array-based telomere copy-number screening make it highly suited for introduction into the clinic as a rapid and sensitive automated diagnostic procedure.
端粒染色体重排可能导致智力迟钝、先天性异常和流产。自动检测涉及端粒的细微缺失或重复对于高通量诊断至关重要，但使用传统细胞遗传学方法时则无法实现。基于微阵列的比较基因组杂交（CGH）通过将差异标记的测试基因组和参考基因组与机器人点样克隆阵列杂交，能够对拷贝数异常进行高分辨率筛选。为了评估该技术在诊断（亚）端粒失衡中的适用性，我们在此描述一项盲法研究，其中将20例已知涉及一个或多个端粒的细胞遗传学异常患者的DNA与一个包含经过验证的一组人类染色体特异性（亚）端粒探针的微阵列进行杂交。在这些微阵列上准确检测到了单拷贝数的增加和减少，并且通过单次杂交，原始细胞遗传学诊断与基于微阵列的CGH诊断之间获得了极佳的一致性。除了先前确定的细胞遗传学变化外，基于微阵列的CGH在研究的20例患者中的3例中还发现了额外的端粒重排。这种基于微阵列的端粒拷贝数筛选的稳健性和简便性使其非常适合作为一种快速、灵敏的自动化诊断程序引入临床。
