Division of Medical Screening and Special Testing, Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA.
Genet Med. 2011 Nov;13(11):913-20. doi: 10.1097/GIM.0b013e3182368a0e.
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.
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.
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.
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.
唐氏综合征的产前筛查已有改善，但由此产生的侵入性诊断程序的数量仍然存在问题。循环游离 DNA 的测量在母体外周血中可能会有所改善。
在高危唐氏综合征的 4664 例妊娠队列中设计了一项盲法、巢式病例对照研究。对 212 例唐氏综合征和 1484 例匹配的正常二倍体妊娠的胎儿核型进行了比较，这些病例均经过内部验证的、基于下一代测序的实验室开发的检测。所有病例都未经过预先检测。主要检测在 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。
唐氏综合征的检出率为 98.6%（209/212），假阳性率为 0.20%（3/1471），13 例（0.8%）检测失败；所有病例均为正常二倍体。在未拆盲之前，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检测性能的影响最大。
当应用于高危妊娠时，测量母体外周血 DNA 可以在非常低的假阳性率下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相关程序引起的胎儿丢失的需求。尽管需要解决实施问题，但证据支持在临床上引入这种检测。
