Posts Tagged ‘edwards syndrome’
Posted March 5, 2012on:
Noninvasive method accurately and efficiently detects risk of Down syndrome
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 statisticalalgorithm, 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 sepa
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.
Trisomy 18 is a syndrome associated with the presence of a third (extra) number 18 chromosome.
Causes, incidence, and risk factors
Trisomy 18 is a relatively common syndrome affecting approximately 1 out of 3,000 live births and affecting girls more than three times as often as boys. Multiple abnormalities are associated with the presence of an extra number 18 chromosome. Many of these abnormalities are not compatible with more than a few months of life. Few infants survive beyond the first year. low birth weight, mental retardation, low-set ears, malformed ears, small jaw (micrognathia), hand abnormalities, congenital heart disease,hernias, and undescended testicle (cryptorchidism). There may be many other abnormalities noted.
Common findings include
- Unusually large uterus during pregnancy
- Low birth weight infant
- Mental deficiency
- Low-set ears
- Small jaw (micrognathia)
- Clenched hands
- Hypoplastic (underdeveloped) fingernails
- Umbilical hernia or inguinal hernia
- Diastasis recti
- Crossed legs (preferred position)
- Congenital heart disease
- Congenital kidney abnormalities
- Coloboma of iris
- Motormental retardation
- Pectus carinatum
Signs and tests
Support Organization for Trisomy 18, 13 and Related Disorders (SOFT)
2982 S Union St
Rochester, NY 14624
Trisomy 18 Support Foundation, Inc.
4301 Connecticut Ave. N.W. Suite 404
Washington, D.C. 20008-2369
The abnormalities of trisomy 18 are generally not compatible with more than a few months of life. Fifty percent of the affected infants do not survive beyond the first week of life. More than 10 children have survived to teenage years, but usually with marked handicaps.
Calling your health care provider
Prenatal diagnosis of trisomy 18 ispossible with an amniocentesis and chromosome studies on amniotic cells. Parents who have a child with translocational trisomy 18 should have chromosome studies, because they are at increased risk for another child with trisomy 18.
Update Date: 8/19/2003
Updated by: Douglas R. Stewart, M.D., Division of Medical Genetics, Hospital of the University of Pennsylvania, Philadelphia, PA. Review provided by VeriMed Healthcare Network.
Trisomy 18 Disorders Menu
Trisomy 18 Support
Trisomy 18 is a rare chromosome abnormality, affecting about one in every 3,000 to 4,000babies, which involves severe mental retardation as well as physical birth defects. Most babies with this condition do not live longer than a few days, weeks, or months; about 70% of fetuses conceived with Trisomy 18 die before birth. Those who do survive are usually small for their age and have a poor suck and weak cry. They have feeding problems, since it is difficult for them to coordinate breathing, sucking, and swallowing. Only about 10% are alive at the time of their first birthday, although some children do live for years. Children with Trisomy 18 who survive past infancy usually do not walk, but some have learned a few words or signs to use in communicating. Some children with Trisomy 18 smile responsively and interact with family members.
In addition to mental retardation, babies with Trisomy 18 have various birth defects. The most common of these are heart defects, a cleft lip (when the upper lip does not form properly), and kidney problems. The babies are often born with their fists clenched; this is due to abnormalities in the nervous system which prevent the hand muscles from receiving proper instructions to move normally.
The problems with Trisomy 18 are caused by anextra chromosome — specifically a third copy of chromosome number 18. Chromosomes, which normally come in pairs – one in each pair from the mother and one from the father — are the packages of genetic material which give the baby the instructions for growth and development. The extra genetic material that a baby with Trisomy 18 receives interferes with these instructions and causes abnormalities in many organs of the body. The extra copy of chromosome 18 was present in either the sperm or the egg which went to form the baby, and this mistake occurred either prior to or just at conception. Many parents wonder why Trisomy 18 occurred, but we know of nothing that either parent could have done that would have caused or prevented this from happening.
It is very unusual for a family to have a second child with Trisomy 18. If you were under 30 years old when pregnant with your baby with Trisomy 18, then there is approximately a 1% chance for another baby to have Trisomy 18. If you were over 30, then your risk is not increased; it is simply the same as that of any other woman your age. Prenatal diagnosis is an option for you in a future pregnancy, even though the risk of recurrence is low.
Mosaic Trisomy 18
Occasionally Trisomy 18 is present in only some of the baby’s cells; this is known as mosaic Trisomy 18; in these cases the outlook is often better than for those babies with full Trisomy 18.
Trisomy 18 can be diagnosed prenatally through CVS or amniocentesis (See CVS/Amnio section) ; it is also one of the conditions screened for in the XAFP program (See XAFP section). Sometimes ultrasound findings provide the first indication that the baby has a problem.
In other cases a baby with Trisomy 18 may be diagnosed shortly after birth. If facial features, a heart defect, or other problems raise the possibility of Trisomy 18, a blood chromosome study will be done to confirm the diagnosis. If a baby is born with Trisomy 18, decisions about care and interventions (such as heart surgery) will have to be made and should be discussed with your baby’s doctor.
If you have just learned during your pregnancy that your baby has Trisomy 18 and are trying to decide whether or not to continue your pregnancy, you will probably not find many sources of information on this condition. There is an organization called SOFT (Support Organization for Trisomy 18, 13, and Related Disorders) which is a group composed of parents who have children with Trisomy 18 and other related conditions, as well as professionals who have an interest in caring for children with those conditions. These parents are strong advocates for their children and emphasize the positive aspects involved in raising a child with Trisomy 18. Parents who continue a pregnancy with a baby with Trisomy 18 or who have a baby born unexpectedly with this condition have found this group to be a great support. Their website can be found at