VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia.
Hum Mutat. 2011 Dec;32(12):1500-6. doi: 10.1002/humu.21581. Epub 2011 Sep 19.
Microarray analysis has provided significant advances in the diagnosis of conditions resulting from submicroscopic chromosome abnormalities. It has been recommended that array testing should be a "first tier" test in the evaluation of individuals with intellectual disability, developmental delay, congenital anomalies, and autism. The availability of arrays with increasingly high probe coverage and resolution has increased the detection of decreasingly small copy number changes (CNCs) down to the intragenic or even exon level. Importantly, arrays that genotype SNPs also detect extended regions of homozygosity. We describe 14 examples of single gene disorders caused by intragenic changes from a consecutive set of 6,500 tests using high-resolution SNP microarrays. These cases illustrate the increased scope of cytogenetic testing beyond dominant chromosome rearrangements that typically contain many genes. Nine of the cases confirmed the clinical diagnosis, that is, followed a "phenotype to genotype" approach. Five were diagnosed by the laboratory analysis in the absence of a specific clinical diagnosis, that is, followed a "genotype to phenotype" approach. Two were clinically significant, incidental findings. The importance of astute clinical assessment and laboratory-clinician consultation is emphasized to optimize the value of microarrays in the diagnosis of disorders caused by single gene copy number and sequence mutations.
微阵列分析在诊断亚微观染色体异常引起的疾病方面取得了重大进展。已经建议将阵列测试作为评估智力残疾、发育迟缓、先天畸形和自闭症个体的“第一级”测试。具有越来越高的探针覆盖率和分辨率的阵列的可用性增加了对越来越小的拷贝数变化（CNC）的检测，直至基因内甚至外显子水平。重要的是，对 SNP 进行基因分型的阵列还可以检测到同一位点的高度同源区域。我们描述了使用高分辨率 SNP 微阵列对连续 6500 次测试中的 14 个由基因内变化引起的单基因疾病的例子。这些病例说明了细胞遗传学检测范围的扩大，超出了通常包含多个基因的显性染色体重排。其中 9 例证实了临床诊断，即遵循“表型到基因型”方法。5 例在没有特定临床诊断的情况下通过实验室分析进行诊断，即遵循“基因型到表型”方法。2 例为临床意义上的偶发发现。强调了敏锐的临床评估和实验室-临床医生咨询的重要性，以优化微阵列在诊断由单基因拷贝数和序列突变引起的疾病中的价值。
