DNA sequencing of maternal plasma to detect Down syndrome: An international clinical validation study
DNA sequencing of maternal plasma to detect Down syndrome: An international clinical validation study
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DOI：
10.1097/gim.0b013e3182368a0e
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发表时间：
2011-11-01
影响因子：
8.8
通讯作者：
Canick, Jacob A.
中科院分区：
文献类型：
--
作者：
Palomaki, Glenn E.;Kloza, Edward M.;Canick, Jacob A.
目的：唐氏综合征的产前筛查已经有所改善，但由此产生的侵入性诊断程序的数量仍然存在问题。测量母体血浆中的循环游离DNA可能会有所改善。方法：在4664例唐氏综合征高危妊娠中设计了一项盲法、巢式病例对照研究。在212例唐氏综合征和1484例匹配的整倍体妊娠中，将胎儿核型分析与内部验证的实验室开发的基于下一代测序的测试进行了比较。以前没有测试过。初步测试在CLIA认证的商业实验室进行，由CLIA认证的大学实验室进行交叉验证。结果如下：唐氏综合征检出率为98.6%（209/212），假阳性率为0.20%（3/1471），13例妊娠检测失败（0.8%），均为整倍体。揭盲前，主要检测实验室还报告了多种替代解释。调整鸟嘌呤胞嘧啶碱基含量的21号染色体计数对提高性能的影响最大。结论：当应用于高危妊娠时，测量母体血浆DNA可以以非常低的假阳性率检测出几乎所有的唐氏综合征病例。这种方法可以大大减少对侵入性诊断程序和伴随程序相关的胎儿损失的需要。尽管需要解决实施问题，但证据支持在临床基础上引入该测试。Genet Med 2011：13（11）：913-920.
Purpose: Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement. Methods: A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory. Results: Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance. Conclusion: When applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis. Genet Med 2011:13(11):913-920.