Down Syndrome: Dragnet techniques in the uterus

20. October 2011
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With the increase in the age of many mothers increases also the risk of having a child with Down syndrome. Invasive tests are risky, but for a biomolecular procedure a blood sample of the pregnant woman is all that is needed. Geneticists might be able to reveal far more than just foetal genetic disorders.

Over the years the risk increases: At the age of 20, only 0.2 percent of all mothers have a baby with trisomy 21, with 45-year-olds it’s well around five percent. Pregnancy in more mature years is no longer so rare: while the percentage of 45-year-olds even in 1990 was 0.8 percent, at present it has reached 4.5 percent. This is in itself not new information, but for this risk group chorionic villus sampling or amniocentesis itself is the first risk: if doctors injure the placenta or amniotic sac, in order to get foetal cells, there is a threat of miscarriage. From a statistical perspective this happens, depending on the study, in each 100th to 200th case – not a good prospect for expectant mothers.

Ultrasound and biomarker

For this reason gynaecologists at the Fetal Medical Foundation (FMF) have developed an alternative test. As part of an ultrasound examination, they measure the nuchal translucency of the unborn child. A blood test of the mother then follows, of special interest are two specific markers: human chorionic gonadotropin and pregnancy-associated plasma protein A, the test result for which is then evaluated along with ultrasound data via their specially designed software “Prenatal Risk Calculation”. More than 85 percent of trisomy 13, 18 and 21 can be detected according to the FMV, as indicated by a study of 70,000 pregnancies. “Nevertheless, the first-trimester screening does not replace the amniocentesis, because using it we can only estimate risks, but not make any diagnoses”, says Dr Christian Thode, a specialist in laboratory medicine in Göttingen, offering something to ponder.

On the prowl in the genome

Research has, after long preparatory developments, found an alternative: Chinese researchers discovered that foetal genetic material can be extracted from the blood of pregnant women – an insight that already extends back to 1997. Human geneticists led by Professor Dennis Lo of the Chinese University of Hong Kong fished from the blood of pregnant women numerous fragments of offspring DNA, with which they were able to initiate precious little. Their search for intact cells proved to be unsuccessful, and so the discovery was at first just put in the files. However with the introduction of Next Generation Sequencing, researchers went back to these old articles. Processes with the highest throughput power and high-capacity computers, combined with bioinformatics analysis, can now, from the bits and pieces of the puzzle presented by the unborn, convey all the information that parents and gynecologists were only able to dream of. And so it was again Dennis Lo who, at the end of 2010 transcribed the complete sequence in the foetal genomic debris: a new chapter in prenatal diagnosis. He did not chose for his studies just any pregnant women randomly. Lo’s first patient had the genetic foundations of beta-thalassemia, a disorder of red blood cells with defects on the 11th chromosome. The unborn child was shown to be a heterozygous mutation carrier, as the geneticists correctly determined from maternal blood on the basis of foetal DNA. 



The working group has also been able to record the same kind of success with Down syndrome. In a pilot study of about 580 pregnant women, trisomy 21 cases were able to be detected by the tenth week with near-certainty. The researchers then verified all the diagnoses using classical karyotyping.

But why put (just about) the whole genome under the microscope? From the perspective of clinicians, such an effort is mostly unnecessary. Since relevant information is hidden in exons of the human genome, ie areas that serve as a blueprint for proteins, it’s only these that have to be shredded and analysed.

Still, the method is not part of routine diagnostics. That could change soon, however, if things go as LifeCodexx AG, a subsidiary of GATC Biotech AG, would like: They are currently refining the method further, clinical tests are also pending. Market readiness is said to be the end of 2011, at the latest early 2012. Then, without risk, the unborn child could be examined as to whether it has Down syndrome or some other trisomy – expectant mothers only need to have blood drawn, in order to have certainty on the subject one way or the other. Researchers and clinicians expect that, consequently, more tests would be conducted and thus there would also be an increase in the number of induced abortions.

Innovation or selection?

Statistically, 90 percent of patients exercise the abortion option following the diagnosis “Down Syndrome”. Numerous people have only been born with the condition, because their mothers had decided against the risky examination of the placenta or amniotic fluid. And so Hubert Hüppe (CDU), in his capacity as Disability Commissioner of the German Federal Government, has reproached the German Federal Ministry of Education and Research (BMBF) for running “disability discrimination of the worst type”. It was after all Annette Schavan’s ministry which supported the development of new diagnostics with about 230,000 €. Hüppe speaks of the new method as “selection“, as a “kind of computer surveillance with the sole aim of sorting out and killing people with a disability”. And the deputy chairman of the CDU /CSU parliamentary group, Johannes Singhammer, urged the BMBF to pull the plug as quickly as possible on the money supply. 



The Ministry has reacted to the scolding: “The criticism by Mr. Hüppe is absurd and also permits the greater risk to mother and child that comes from the current diagnostic procedures“, said the Parliamentary State Secretary Thomas Rachel (CDU). In his words, “it is not ethical to not want to promote the further development of a research method utilised in Germany, which can better protect the unborn child and expectant mother.” Rachel also gets approval from Germany’s Professional Association of Gynaecologists. “The couples concerned have their own conscience“, said Dr. Werner Harlfinger. He made reference to the existing entitlement to have such investigations as amniocentesis carried out. Notwithstanding that the new molecular biology technique can provide much more, limits are still required.

Desired child made-to-order

The sequencing of foetal DNA scientifically allows characteristics such as hair colour or eye colour to be identified. This is not quite a new topic: the Bundestag recently legalised preimplantation genetic diagnosis (PGD) after heated debates – in justified exceptional cases, it was made to be understood. Embryos conceived by normal means, however, could theotetically soon be submitted for testing more thoroughly, as hardly any expert seriously believes the diagnostic procedure of LifeCodexx would be limited to trisomies. Other genetic diseases, such as muscular dystrophy, cystic fibrosis, Huntington’s disease or familial adenomatous polyposis, are next on the wish list of researchers. After that follow the genetic risk of developing cancer, Alzheimer’s or Parkinson’s disease, age-cardiovascular disease or type 2 diabetes.

This much is certain: If the techniques are available, they will sooner or later also be put in use. A clear acknowledgement by the medical profession would be urgently needed, such as has already happened for the PGD: Researchers have already voted for a resolution by a large majority, which considers in-vitro fertilisation with PGD, in certain cases, to be “ethically less problematic than a preanatodiagnostic analysis carried out with termination of pregnancy as a consequence”. Göttingen Neurobiology professor Dr. Gerald Huether on the other hand points to the body’s alteration processes and reminded those at the last Capital Congress Medicine and Health: Even a few years ago nobody believed that humans with trisomy 21 were capable of being educated. Today they’ve finished high school and have been able to study.

Besides the ethical dilemma, economic issues are also present – the requested services for molecular diagnostics, from the start, have to definitely come from one’s own pocket. Thus, the number of risky amniocentesis can be reduced to zero, which is a premise that will pave the path for this method to sooner or later make its way into the catalogue of health insurance benefits.

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