Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders
Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders
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DOI：
10.1038/gim.2011.65
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发表时间：
2012-06-01
影响因子：
8.8
通讯作者：
Suchy, Sharon
中科院分区：
文献类型：
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作者：
Aradhya, Swaroop;Lewis, Rachel;Suchy, Sharon
目的：孟德尔疾病最常见是由 DNA 测序可识别的突变引起的。外显子缺失和重复可能无法通过测序检测到，并且它们在大多数孟德尔疾病中的频率未知。方法：我们设计了一种阵列比较基因组杂交 (CGH) 测试，探针位于 589 个基因的外显子区域。对 3,018 名患者的 219 个基因进行了靶向测试。我们通过检测 136 种常染色体显性遗传、53 种常染色体隐性遗传和 30 种 X 连锁疾病，首次证明了外显子级阵列 CGH 在大型临床队列中的实用性。结果：总体而言，在 53 个基因中发现了 98 个缺失和 2 个重复，对应的检出率为 3.3%。大约 40% 的阳性结果是仅删除了一两个外显子。几种常染色体显性遗传疾病的缺失频率很高，检出率为 2.9%。对于常染色体隐性遗传疾病，通常在通过测序鉴定出单个突变后进行阵列 CGH。在 138 名接受隐性遗传疾病检测的个体中，10.1% 存在基因内缺失。对于 X 连锁疾病，313 名患者中有 3.5% 携带缺失或重复。结论：我们的结果表明，外显子水平阵列 CGH 为基因内拷贝数分析提供了可靠的选择，并且应常规补充孟德尔疾病的序列分析。
Purpose: Mendelian disorders are most commonly caused by mutations identifiable by DNA sequencing. Exonic deletions and duplications can go undetected by sequencing, and their frequency in most Mendelian disorders is unknown.Methods: We designed an array comparative genomic hybridization (CGH) test with probes in exonic regions of 589 genes. Targeted testing was performed for 219 genes in 3,018 patients. We demonstrate for the first time the utility of exon-level array CGH in a large clinical cohort by testing for 136 autosomal dominant, 53 autosomal recessive, and 30 X-linked disorders.Results: Overall, 98 deletions and two duplications were identified in 53 genes, corresponding to a detection rate of 3.3%. Approximately 40% of positive findings were deletions of only one or two exons. A high frequency of deletions was observed for several autosomal dominant disorders, with a detection rate of 2.9%. For autosomal recessive disorders, array CGH was usually performed after a single mutation was identified by sequencing. Among 138 individuals tested for recessive disorders, 10.1% had intragenic deletions. For X-linked disorders, 3.5% of 313 patients carried a deletion or duplication.Conclusion: Our results demonstrate that exon-level array CGH provides a robust option for intragenic copy number analysis and should routinely supplement sequence analysis for Mendelian disorders.