Category Archives: Genetic Medicine

Scientists map babys genetic code in womb

By John von Radowitz

Friday, June 08, 2012

An unborn babys whole genetic code has been mapped in the womb using DNA taken from its parents.

The technique could in future make it possible to swiftly scan for some 3,500 genetic disorders before birth, without physically disturbing either foetus or mother.

But scientists acknowledge the ability to sequence a babys whole genome in the womb has as yet unresolved ethical implications.

It could produce a wealth of data relating to a babys future health. At the same time, difficult questions may be raised about the moral case for termination.

Most pre-natal genetic screening currently involves tapping fluid from the foetal sac, or taking placental samples. Such invasive methods can only identify a small number of birth defects including Downs syndrome, and spina bifida.

They also pose risks for both mother and child. But there are thousands of rarer genetic conditions that are seldom spotted until they start producing symptoms.

The new research involved analysing DNA shed by the foetus and floating in the mothers bloodstream. Blood sample DNA from the mother was also studied as well as DNA extracted from the fathers saliva.

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Scientists map baby’s genetic code in womb

SEATTLE -- Researchers at the University of Washington have assembled the first comprehensive genetic map of an unborn child -- a development that could help usher in a new era of prenatal testing.

By analyzing fetal DNA circulating in the mother's blood, the scientists were able to sequence the baby's genome 18 weeks into the pregnancy. The technique also worked at eight weeks, with slightly lower sensitivity.

Because the approach requires only a blood sample from the mother and saliva from the father, it poses none of the miscarriage risk associated with invasive tests such as amniocentesis. And while most existing prenatal tests are designed to check for single disorders, including Down syndrome, a full-gene scan has the power to reveal a wide range of potential problems before birth, said lead author Jacob Kitzman, a doctoral student in genetics.

"It's much more comprehensive."

The procedure is still several years away from commercialization, project leader Jay Shendure said.

But the UW study, published in the June 6 issue of Science Translational Medicine, marks a significant step forward in technology that's been developing over the past several years -- and which worries some people, said Marcy Darnovsky of the Center for Genetics and Society in Berkeley, Calif.

"I think it's a game-changer," she said. Cheap, safe genome sequencing could give parents the power to practice a kind of eugenics, preselecting children based on desirable traits.

"It could become a routine part of prenatal testing ... which raises questions about what people will do with the information," Darnovsky said.

Shendure cautioned against expecting too much -- at least in the near future. Scientists may be able to sequence the 3 billion DNA units that make up each person's genetic heritage, but they still don't understand the genetic basis of most common diseases.

"The capacity of genomics to generate data is outstripping our ability to interpret it in useful ways," he said.

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Researchers assemble genetic map of an unborn child

By contrast, the scientists say their new test would identify far more conditions, caused by genetic errors.

However, they warned it raised many ethical questions because the results could be used as a basis for abortion.

These concerns were last night amplified by pro-life campaigners, who said widespread use of such a test would inevitably lead to more abortions.

The American scientists were able to map the babys genetic code principally from tiny traces free-floating DNA, which makes its way into the mothers blood.

Blood sample DNA from the mother was also studied as well as DNA extracted from the father's saliva.

Fitting pieces of the genetic jigsaw together, scientists in the US were able to reconstruct the entire genetic code of an unborn baby boy.

They were then able to see what spontaneous genetic mutations had arisen.

Such natural mutations - called de novo mutations - are responsible for the majority of genetic defects.

By checking their prediction of the babys genetic code with actual DNA taken after the birth, the team from the University of Washington in Seattle, found they were able to identify 39 of 44 such mutations in the child.

De novo mutations are thought to play a role in a number of complex conditions such as autism and schizophrenia.

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Unborn babies could be tested for 3,500 genetic faults

Researchers at the University of Washington have sequenced the entire genome of a fetus. The scientific advance could help detect certain diseases in the womb, but some experts worry that the trove of genetic information may prove more scary and overwhelming than useful.

Suspended in the blood of a pregnant woman along with some added information from a dad-to-bes saliva lurks enough fetal DNA to map out an unborn babys entire genetic blueprint.

It may sound like something conjured by Jules Verne, but it happened at the University of Washington: a professor and his graduate student used DNA samples from the parents of a baby boy who was still in utero and reconstructed his entire genetic makeup from A to Z.

The account, published Wednesday in Science Translational Medicine, takes prenatal testing to new heights, promising a motherlode of genetic information about a child who had not even been born along with a corresponding trove of data that even experts dont yet know how to interpret.

Jacob Kitzman, lead author and a graduate student in the department of genome sciences at the University of Washington (UW), was excited but cautious about his teams achievement. There have been a lot of steps toward this, but this is the first time capturing the whole genome, says Kitzman. The fact that this technology is now on the path to becoming clinically feasible is a good opportunity for a broader discussion of the implications.

Figuring out how to communicate the vast cache of information uncovered by genome sequencing remains controversial, since much of it still isnt clinically useful. But although researchers dont understand the significance of the entirety of the information revealed through whole-genome sequencing, they do know that certain genes are responsible for Mendelian, or more simple, single-gene disorders that includes more than 3,000 conditions such as cystic fibrosis, Tay-Sachs disease and some muscular dystrophies that affect 1% of pregnancies. Prenatal sequencing would allow parents to learn before delivery if their child has one of these diseases, many of which are debilitating or fatal. While genetic screening of parents before pregnancy can also identify carriers, and an increasing number of prenatal DNA-based tests can determine early in pregnancy whether developing babies have specific conditions such as Down syndrome, whole-genome sequencing is the most sophisticated way to examine a persons entire genetic code.

(MORE:Down Syndrome: With Breakthroughs in Testing, a Choice Becomes Tougher)

Prenatal genome sequencing could potentially replace more invasive procedures such as amniocentesis or chorionic villus sampling to detect recessive Mendelian disorders on average, we all carry 20 to 30 recessive genes but it is not yet precise enough to take the place of these tests when looking for other chromosomal conditions. Nor is it a foolproof gauge of risk for many other complex diseases a category that includes most cancers and common conditions such as diabetes and heart disease because theyre influenced by multiple genes and environmental factors. Great, says Thomas Murray, president of the Hastings Center bioethics institute, we can sequence the genome of a fetus. What the hell does it tell us? Much less than most people probably believe.

Kitzman concurs. Its a really big challenge for the field, figuring out how to communicate to clinicians not only the results but the uncertainty that goes along with those results, he says. Theres no easy answer.

In this particular situation, Kitzman and Jay Shendure, an associate professor of genome sciences at UW, sidestepped the thorny issue of assessing disease risk and sharing that information with parents because the expectant couple was anonymous. Kitzman doesnt know their identity, only that they consented to have their biological samples used for genome sequencing. Their son was born healthy and full-term.

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Genetic Motherlode: Scientists Decode an Unborn Baby's DNA

Prospective parents might soon be able to screen their unborn babies for thousands of genetic disorders, according to a study published by Science Translations Medicine.

This is potentially a two-edged sword, according to experts: Althoughthe testmight pick up more curable conditions earlier, some worry that it may lead to more abortions.

American scientists were able to map the babys genetic code form tiny traces of free-floating DNA in blood from the babys mother, who was 18 weeks pregnant. They were also able to pinpoint if the mutations came from the mother or fathers side.

If the technique is refined and the technology becomes inexpensive, as many experts predict, this type of prenatal testing could allow doctors to screen unborn babies for 3,500 genetic disorders by taking a blood sample from the mother and a swab of saliva from the father.

Now, the only genetic disorder routinely testing is Down Syndrome.

On the positive side, picking up genetic problems early may lead to better treatments, sometimes while the baby is still a fetus, sometimes right after birth and that might prevent complications, said NBC4 health expert Dr. Bruce Hensel.

It might give peace of mind if (parents) dont find problems. On the other hand, it could lead to dilemmas what do you do about them can you treat them, might it lead to more abortions? Hensel added.

The genetic predictions in the study were confirmed by analyzing umbilical cord blood collected at the babys birth.

The test is not being used yet, and experts said the methods will have to refined before the screenings are widely used.

This is only preliminary. Well need to see if the test is consistently accurate, because were looking at the mothers blood, not the babys, and it might not be 100 percent accurate, Hensel said. You dont want to find potential genetic disorders that dont pan out to be a real problem at all.

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Study: Testing Unborn Babies for Genetic Disorders

ScienceDaily (June 5, 2012) Using a noninvasive test on maternal blood that deploys a novel biochemical assay and a new algorithm for analysis, scientists can detect, with a high degree of accuracy, the risk that a fetus has the chromosomal abnormalities that cause Down syndrome and a genetic disorder known as Edwards syndrome. The new approach is more scalable than other recently developed genetic screening tests and has the potential to reduce unnecessary amniocentesis or CVS.

Two studies evaluating this approach are available online in advance of publication in the April issue of the American Journal of Obstetrics & Gynecology (AJOG).

Diagnosis of fetal chromosomal abnormalities, or aneuploidies, relies on invasive testing by chorionic villous sampling or amniocentesis in pregnancies identified as high-risk. Although accurate, the tests are expensive and carry a risk of miscarriage. A technique known as massively parallel shotgun sequencing (MPSS) that analyzes cell-free DNA (cfDNA) from the mother's plasma for fetal conditions has been used to detect trisomy 21 (T21) pregnancies, those with an extra copy of chromosome 21 that leads to Down syndrome, and trisomy 18 (T18), the chromosomal defect underlying Edwards syndrome. MPSS accurately identifies the conditions by analyzing the entire genome, but it requires a large amount of DNA sequencing, limiting its clinical usefulness.

Scientists at Aria Diagnostics in San Jose, CA developed a novel assay, Digital Analysis of Selected Regions (DANSR), which sequences loci from only the chromosomes under investigation. The assay requires 10 times less DNA sequencing than MPSS approaches.

In the current study, the researchers report on a novel statistical algorithm, the Fetal-fraction Optimized Risk of Trisomy Evaluation (FORTE), which considers age-related risks and the percentage of fetal DNA in the sample to provide an individualized risk score for trisomy. Explains author Ken Song, MD, "The higher the fraction of fetal cfDNA, the greater the difference in the number of cfDNA fragments originating from trisomic versus disomic [normal] chromosomes and hence the easier it is to detect trisomy. The FORTE algorithm explicitly accounts for fetal fraction in calculating trisomy risk."

To test the performance of the DANSR/FORTE assay, Dr. Song and his colleagues evaluated a set of subjects consisting of 123 normal, 36 T21, and 8 T18 pregnancies. All samples were assigned FORTE odd scores for chromosome 18 and chromosome 21. The combination of DANSR and FORTE correctly identified all 36 cases of T21 and 8 cases of T18 as having a greater than 99% risk for each trisomy in a blinded analysis. There was at least a 1,000 fold magnitude separation in the risk score between trisomic and disomic samples.

In a related study, researchers from the Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, University of London and the University College London Hospital, University College London, provided 400 maternal plasma samples to Aria for analysis using the DANSR assay with the FORTE algorithm. The subjects were all at risk for aneuploidies, and they had been tested by chorionic villous sampling. The analysis distinguished all cases of T21 and 98% of T18 cases from euploid pregnancies. In all cases of T21, the estimated risk for this aneuploidy was greater than or equal to 99%, whereas in all normal pregnancies and those with T18, the risk score for T21 was less than or equal to 0.01%.

"Combining the DANSR assay with the FORTE algorithm provides a robust and accurate assessment of fetal trisomy risk," says Dr. Song. "Because DANSR allows analysis of specific genomic regions, it could be potentially used to evaluate genetic conditions other than trisomy. The incorporation of additional risk information, such as from ultrasonography, into the FORTE algorithm warrants investigation."

Kypros H. Nicolaides, MD, senior author of the University of London study, suggests that fetal trisomy evaluation with cfDNA testing will inevitably be introduced into clinical practice. "It would be useful as a secondary test contingent upon the results of a more universally applicable primary method of screening. The extent to which it could be applied as a universal screening tool depends on whether the cost becomes comparable to that of current methods of sonographic and biochemical testing."

Dr. Nicolaides also notes that the plasma samples were obtained from high-risk pregnancies where there is some evidence of impaired placental function. It would also be necessary to demonstrate that the observed accuracy with cfDNA testing obtained from the investigation of pregnancies at high-risk for aneuploidies is applicable to the general population where the prevalence of fetal trisomy 21 is much lower. "This may well prove to be the case because the ability to detect aneuploidy with cfDNA is dependent upon assay precision and fetal DNA percentage in the sample rather than the prevalence of the disease in the study population," he concludes.

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Noninvasive genetic test for Down syndrome and Edwards syndrome highly accurate