- For Whom?
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PrenatalSAFEis a test indicated for patients with:
• Maternal age-related risks (≥35 years)
• Ultrasound finding(s) suggestive of aneuploidy
• Personal or family history of chromosomal aneuploidy
• One of the partners with a balanced chromosome 13 or 21 Robertson translocation
• A positive first trimester test (Bi-Test)
• Low-risk pregnanciesCan be used for:
• Pregnancies where invasive procedures are not recommended (risk of spontaneous abortions)
• Pregnancies that are natural or assisted homologous or heterologous
• Twin pregnancies that are natural or assisted. In these pregnancies it is not possible to perform tests on X and Y, but only tests on chromosomes 13, 18 and 21
• Prior normal pregnancies - What is diagnosed?
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PrenatalSAFEis a non invasive prenatal test that detects common chromosomal aneuploidies on chromosome 21 (Down Syndrome), chromosome 18 (Edwards Syndrome) and chromosome 13 (Patau Syndrome) and those of the X and Y sexual chromosomes such as: Turner Syndrome, Klinefelter Syndrome and Jacobs Syndrome, by analyzing fetal DNA in circulation.
PrenatalSAFEoffers a further second level of testing that diagnoses structural chromosomal alterations, among which a few common microdeletion syndromes (DiGeorge Syndrome, Cri-du-chat Syndroma, Prader-Willi Syndrome, Angelman Syndrome, 1p36 deletion Syndrome, WolfHirschorn Syndrome), and Trisomy 9 and 16.
PrenatalSAFEcan find chromosomal aneuploidies even on low quantities of fetal DNA (2%), in comparison to other tests that require >4% of fetal DNA.
PrenatalSafe®
A non invasive prenatal test (NIPT). A test that detects chromosomal aneuploidies by circulating fetal DNA analysis
Procedure
Fetal DNA circulates in maternal blood and is detectable as of the fifth week of pregnancy, its concentration increases in the following weeks and disappears right after giving birth.
The PrenatalSAFEtest is performed simply by drawing a blood sample as of the tenth week of pregnancy.
Cell-free Fetal DNA is then isolated from the maternal plasma through a complex laboratory procedure.
After this, using an advanced technological process called "Massively Parallel DNA Sequencing", chromosomal fetal DNA regions over the entire genome using the ILLUMINA Next Generation Sequencing (NGS) sequencers are sequenced at high reading depth (roughly 30 million sequences), and then with an advanced bioinformatic analysis the sequenced chromosomes are quantified
Benefits
SENSITIVE
Can identify chromosomal aneuploidies even on low quantities of fetal DNA (2%), in comparison to other tests that need > 4% fetal DNA.
SIMPLE
A simple blood sample is drawn from the pregnant mother from which circulating fetal DNA is analyzed.
SAFE
A non invasive test therefore risks of aborting during traditional prenatal invasive diagnostic techniques such as amniocentesis or chorionic villus sampling are nullified.
RELIABLE
A reliability of over 99% in identifying Trisomy 21, Trisomy 18 and Trisomy 13 and 95% in identifying Monosomy X and a percentage of false positives <0.1%.
FAST
Thanks to the new high resolution FAST Technology results are ready in 3 working days with the same sensitivity and accuracy parameters.
Fetal fraction assessment
Assessing fetal fraction (FF), the percentage of fetal cfDNA in the plasma sample against total cfDNA is an important value when performing NIPT testing since very low FF can be difficult for determining aneuplodies and therefore produce false negatives.
For this reason some NIPT testing methods today have as a cut-off 4% of fetal fraction. Values under this cut-off, are reported as an inconclusive result due to the low quantity of fetal DNA and a new blood sample is required.
A recent study 4,5 was designed to determine Prenatalsafe’s actual LOD (limit of detection) for Trisomy 21,18 and 13 and to evaluate the test results on low clinical fetal fraction (<4%) samples. The study showed that the main chromosomal aneuploides can be assessed with Prenatalsafe at FF≥2%. This result has allowed to reduce the incidence of inconclusive results due to low fetal fractions, from 8,7% (with a cut-off of 4% FF) to 2.2% (with a cut-off of 2% FF).
Had a cut-off of FF>4% been used, 23,4% of aneuploidies wouldn’t have been detected.
The same study showed that the incidence of aneuploidies is 6 times higher in samples with low fetal fractions (2%<FF<4%) in comparison to samples with FF>4%. An increased incidence of chromosomal aneuploidies, 4 to 10 times higher, has been reported in other studies with inconclusive result samples due to low fetal fraction (<4%) 6,7. Therefore using the FF>4% as a cut-off, samples with the highest risk of aneuploidies are excluded.
The study underlines the importance of using an NIPT technology able to analyze samples with low FF (2%<FF<4%), to lower the incidence of recalls, to identify as soon as possible pregnancies with high risk of aneuploidies.
Bibliography
1. Ashoor G, Poon L, Syngelaki A, et al. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: effect of maternal and fetal factors. Fetal Diagn Ther 2012; 31:237-43. 2. Canick JA, Palomaki GE, Kloza EM, et al. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn 2013;33:667-74. 3. Benn P, Cuckle H. Theoretical performance of non-invasive prenatal testing for chromosome imbalances using counting of cell-free DNA fragments in maternal plasma. Prenat Diagn. 2014; 34:778-83 4. Fiorentino F, Spinella F, Bono S, Pizzuti F, Mariano M, Polverari A, Duca S, Cottone G, Nuccitelli A, Sessa M, Baldi M. Feasibility of noninvasive prenatal testing for common fetal aneuploidies in maternal serum with low levels circulating fetal cell- free DNA fraction. Prenat Diagn 2015; 35 Suppl. 1: pag 1 5. Bono S, Pizzuti F, Mariano M, Polverari A, Duca S, Cottone G, Nuccitelli A, Sessa M, Spinella F, Baldi M, Fiorentino F. Massively Parallel Sequencing (MPS) reliably identifies trisomy 21, 18, and 13 in maternal plasma with low-level fetal cell-free DNA fractions. Poster presentation from the European Society of Human Genetics (ESHG) meeting Glasgow 2015. 6. Pergament E, Cuckle H, Zimmermann B, et al. Single-nucleotide polymorphism-based noninvasive prenatal screening in a high-risk and low-risk cohort. Obstet Gynecol. 2014;124 (2 Pt 1):210-8. 7. Norton ME, Jacobsson B, Swamy GK, et al. Cell-free DNA analysis for non invasive examination of trisomy. N Engl J Med. 2015;372:1589-97.
If PrenatalSAFEhas a negative result
Absence of chromosomal aneuploidy or microdeletion syndrome:
Means that the fetus doesn’t have any aneuplodies referring to the investigated chromosomes (21, 18, 13, X or Y) and if investigated (9,16) and/or doesn’t show any microdeletions. There is also a chance that the sample submitted will not show optimal results; in this case a second sample may be requested to repeat the test. In other cases the result could be borderline and there is a suspected chromosomal aneupolidy which has to be confirmed by invasive prenatal testing.
If PrenatalSAFEhas a positive result
Presence of chromosomal aneuploidy or microdeletion syndrome:
Means that the fetus has detected an aneuploidy or microdeletion referring to one (or more) of the investigated chromosomes (21, 18, 13, X or Y) and if investigated (9,16). The test result means that the fetus shows the chromosomal condition indicated but doesn’t guarantee that the fetus has the condition. Follow up testing (such as amniocentesis or chorionic villus sampling) is recommended to confirm the result.
Accuracy and testing limit
In preclinical validation studies the test shows an accuracy greater than 99% in identifying Trisomy 21, Trisomy 18 and Trisomy 13, and 95% in identifying Monosomy X, with < 0.1% of false positives. Even though the test is very accurate one must always keep in mind its limits described as following.
The test has been validated on single or twin pregnancies, monozygotic or dizygotic, at least 10 weeks of pregnancy and cannot exclude all possible fetal chromosomal abnormalities, it evaluates only chromosome 13,18,21, X and Y aneuploidies. Therefore the test does not substitute prenatal invasive diagnosis. It is not able to identify balanced rearrangements, alterations, mosaicisms, point mutations, methylation defects, polyplodies, it doesn’t show hereditary genetic diseases with nonmendelian inheritance.
A NEGATIVE result – Absence of chromosomal aneuploidy the chance that the fetus has an aneuploidy for the examined chromosomes is greatly reduced but it can’t guarantee that they are normal or that the fetus is healthy. One cannot perform this test on women who themselves carry aneuploidies.
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