[学术研究]国家科学院院刊(PNAS)关于无创唐氏综合征的介绍

每1000例活产婴儿就会有9例是非整倍体或其他染色体异常。当胎儿21号染色体为3条时,就会出现唐氏综合症。目前检测染色体数目异常的方法多为有创方法,如通过绒膜绒毛取样和羊膜穿刺术获得胎儿细胞,这些方法可能伤害到正在发育中胎儿。


有研究显示,母体血液中存在胎儿的完整细胞,这一发现吸引了大批科学家由此途径寻找检测胎儿遗传缺陷的新方法。然而,母体血液的强大背景无疑对胎儿细胞的检测造成了巨大障碍。孕妇的血液中含有自由浮动的DNA,其中有不足10%来自胎儿。
最近,美国斯坦福大学医学院Stephen Quake等利用鸟枪法测序开发了一种用于发现胎儿非整倍体的无创检验模式。该研究组通过扩增小段DNA,检测母体血液中小片段DNA数量,并与母体染色体染色体进行对比,若存在表达增高或降低的DNA,提示来源于胎儿非整倍体。该研究组已采用这一模式成功检测出9例21三体(唐氏综合症)、2例18三体(Edward综合症)和1例13三体(Patau综合症)。并且他们的结果中,可以很清楚地从最常见的非整倍体中识别出21号染色体的非整倍体。
该研究组指出,随着基因测序费用的下降,这种方法可能很快成为一种代替目前有创检验的廉价和更安全的方法。

Blood Test for Mom Picks Up Down Syndrome in Fetus
A technology guru may have solved a problem that has long vexed obstetricians: how to test for Down syndrome without poking a needle into the womb. By sequencing the fetal DNA floating in a mothers blood, bioengineer Stephen Quakes team at Stanford University in Palo Alto, California, detected nine cases of the disease with 100% accuracy. If this small study holds up in larger trials, the test could become routine for expectant mothers.
Down syndrome is caused by an extra copy of chromosome 21. It results in mental retardation and other health problems, and some women choose to abort Down syndrome fetuses. Although there is a noninvasive screening test that indicates the likelihood a fetus has Down syndrome, pregnant women who want a definitive answer currently have two choices: amniocentesis, which involves inserting a needle into the uterus to withdraw fluid, or another procedure that extracts a piece of placental tissue. These tests, done at about 10 to 16 weeks, are 99% accurate but cost about $1000 and in rare cases can cause miscarriage. As a result, usually only women over 35 who are at higher risk for carrying a Down baby get tested.
In the past decade, researchers have developed prenatal tests for gender and Rh blood group based on testing for mutations in fragments of fetal DNA circulating in the blood of pregnant women (Science, 2 September 2005, p. 1476). But detecting disorders such as Down syndrome using maternal blood has been tougher because the test has to spot an extra chromosome, and the mothers DNA swamps out the fetuss DNA. In the most advanced approach, the company Sequenom, based in San Diego, California, is using messenger RNA produced by the placenta to detect Downs. However, the test is only a screen because it relies on DNA markers on chromosome 21 that vary by ancestry, and it misses about 7% of cases in the U.S. population.
Quakes team tried a brute-force approach to circumvent this problem: They put maternal blood samples through a DNA-sequencing machine. Although the researchers only sequenced about 2% of the mothers and fetuss genome, this was enough data to distinguish levels of chromosome 21 in mothers carrying a Down syndrome baby from those with a normal fetus as early as 14 weeks. In all nine Down syndrome cases tested but not six normal cases, this ratio was greater than one–indicating that the condition was present. The technique also detected three cases of other chromosomal disorders that lead to abnormal development, Quakes group reports online today in theProceedings of the National Academy of Sciences.
The test cost $700 per sample, but that price should come down with newer sequencing technologies, notes Quake, who hopes to see the approach commercialized. “I think its going to get better and better,” agrees Department of Energy medical geneticist Edward Rubin, who says Quakes paper was the talk of a recent genome meeting in Boston.
Fetal testing experts are also impressed: “The results are astonishing,” says molecular biologist Sinuhe Hahn of Basel University Hospital in Switzerland. Hahn and others say its too soon to know, however, whether the test will prove superior to Sequenoms. It needs to be studied on a much larger scale to be sure it can pick up all of the one in 1000 Down syndrome births in the general population, says Diana Bianchi of Tufts University in Boston. Even so, she says, the study is “a significant advance.”