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Fetal & Maternal Healthcare
Figure 3: Trisomy 21 Detected by QF-PCR
For many years, non-invasive prenatal diagnosis (i.e. diagnosis based
on testing maternal blood) has been hailed as the ‘Holy Grail’ of obstetric
care. Both whole fetal cells and free fetal DNA are known to be
present in the maternal circulation, but at extremely low levels.
21,22
D21S1435 D21S11 D21S1437 D13S634 D18S535
Progress towards this goal has been slow; non-invasive tests are
available, for instance for Rhesus factors,
23,24
Y chromosome sequences,
25
and some paternal-specific mutations,
26
where the target of the test
is not present in the mother’s genome and can therefore be amplified,
D18S391 D13S325 D13S386 D13S305
for instance using realtime PCR, with no maternal background.
Down syndrome, however, is a much greater challenge, as the sequences
in the fetal copies of chromosome 21 are also present in the mother,
D18S978 D12S1411
D18S390 D13S628
and the quantification of relative copy number to establish the presence
of three chromosomes in the fetus is hampered by the very
high background of maternal DNA. It is very likely that technology
D21S1409 D13S252 D18S819 will eventually emerge to circumvent this problem and provide an
accurate non-invasive test for Down syndrome, but invasive testing
STR marker names are given below each peak. Chromosome 21 markers all show either three alleles or 1:2/2:1
may still be needed for confirmation prior to termination of pregnancy.
peak area ratios. Markers for chromosomes 13 and 18 show uninformative (single-allele) or 1:1 peak area ratios.
For fetuses with serious anatomical abnormalities detected by
unknown significance, and will result in the same problems as karyotype ultrasonography, invasive testing and karyotype analysis would still
analysis in terms of clear patient information and counseling. There is much be required.
work to be done in testing microarrays on postnatal samples—for example,
children with unexplained developmental syndromes—before applying this The Future
technique to testing samples from vulnerable pregnant women. Looking further ahead, increasing procedure skill may lead to invasive
sampling free of the risk of miscarriage and, hence, no need for eligibility
Targeted Testing criteria for testing. All women concerned about having a Down syndrome
In prenatal diagnosis, there is a strong argument for targeted testing for baby could have a diagnostic test without the need and expense of
pregnancies at increased risk of Down syndrome, with QF-PCR being the ultrasound and metabolite screens; the much cheaper QF-PCR test would
stand-alone test. For pregnancies where the fetus has anatomical make this option financially viable, even in a state-funded health service.
abnormalities, QF-PCR to exclude the viable aneuploides should be followed Detailed ultrasound examination at around 20 weeks gestation (or earlier,
either by karyotyping or by microarray testing (once thoroughly validated), with advances in ultrasound technology) would identify anatomically
as either of these techniques may provide information on the reasons for abnormal fetuses. Finally, changes in societal attitudes to Down syndrome
the fetal abnormalities and help to inform the parents in their decision and other disabling conditions may in time lead to a reduction in demand
on the future of the pregnancy. for prenatal diagnosis. ■
1. Human Genetics Commission, Choosing the Future: genetics and National Health Service and implications for the future of prenatal following maternal serum screening, Prenat Diagn,
reproductive decision making, 2004. diagnosis, Lancet, 2001;358(9287):1057–61. 2001;21(7):553–7.
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1989;320(10):609–17. 13. Leung WC, Lau ET, Lao TT, Tang MH, Can amnio-polymerase chain 21. Chiu RW, Lo YM, Application of fetal DNA in maternal plasma for
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on the live birth prevalence of Down syndrome in New York State, 15. Wilson J, Jungner G, Principles and practice of screening for time PCR using cell free fetal DNA in maternal plasma, Swiss Med
1983–1992, Prenat Diagn, 1996;16(11):991–1002. disease, Public Health Paper, Number 34, Geneva: World Health Wkly, 2001;131(5-6):70–74.
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12 US OBSTETRICS AND GYNECOLOGY 2007
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