Non-invasive Fetal Trisomy Test Research Articles

Non-invasive fetal trisomy (NIFTY) test in prenatal diagnosis

NIFTY (Non-invasive Fetal Trisomy Test) is a non-invasive prenatal test which is used for diagnosing fetal trisomy. The test is based on the analysis of cell free fetal DNA (cffDNA) present in the plasma and serum of a pregnant woman. NIFTY allows to detect fetal trisomy of chromosomes 13, 18, 21, X and Y and also X monosomy. Abnormal NIFTY results still need to be verified using other diagnostic techniques. However the sensitivity of NIFTY for trisomy 21, 18 and 13 is estimated at 99%, 97% and 79% respectively with false positive rate for all examined trisomies and X monosomy of < 1%. NIFTY is currently available in Poland as a commercial service, used as a good screening test for common trisomies (apart from ultrasound and biochemical tests) in the case of patient anxiety and in situation when the patient does not consent to invasive prenatal diagnostic tests. The sensitivity and specificity of NIFTY will most likely be improved as laboratory methods develop, and after a sufficiently large group of pregnant patients has been tested. Therefore, this test may soon become the primary diagnostic tool for common trisomies, allowing to avoid invasive prenatal testing in this indication. With high probability cffDNA obtained from the serum of pregnant women will also be used with time in the diagnosis of fetal structural chromosomal aberrations and other genetic changes. The aim of our study is to present a new diagnostic method.

Non-invasive prenatal diagnosis of the most common aneuploidies with cell-free fetal DNA in maternal serum – preliminary results

The aim of the study was to present initial results of non-invasive prenatal diagnosis of common aneuploidies of chromosomes 21, 18 and 13 based on cell-free fetal DNA in maternal serum in high-risk patients, and to compare the results with routine karyotyping. Before the invasive procedure, 10 ml of peripheral blood from 10 patients was collected to isolate cell-free fetal DNA and to perform a non-invasive fetal trisomy test (NIFTY provided by Beijing Genomics Institute, BGI, Shenzen, China). Three out of 10 samples showed an abnormal karyotype in traditional karyotyping. There were 9 conclusive NIFTY results. NIFTY detected 1 out of 2 trisomies 18. The quantity of cell-free fetal DNA in maternal plasma in the second probe with trisomy 18 was unsatisfactory fora conclusive NIFTY result. In 1 case traditional karyotyping revealed mosaicism impossible to detect with NIFTY

Response to ”concerns about the statistical methodology described in the ‘Clinical application of massively parallel sequencing‐based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11 105 pregnancies with mixed risk factors’”

Response to ”concerns about the statistical methodology described in the ‘Clinical application of massively parallel sequencing‐based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11 105 pregnancies with mixed risk factors’”

Comment on “Clinical application of massively parallel sequencing‐based prenatal non‐invasive fetal trisomy test for trisomies 21 and 18 in 11 105 pregnancies with mixed risk factors”

Objective To report the performance of massively parallel sequencing (MPS) based prenatal noninvasive fetal trisomy test based on cell-free DNA sequencing from maternal plasma in a routine clinical setting in China. Method The MPS-based test was offered as a prenatal screening test for trisomies 21 and 18 to pregnant women in 49 medical centers over 2years. A total of 11263 participants were recruited and the MPS-based test was performed in 11105 pregnancies. Fetal outcome data were obtained after the expected date of confinement. Results One hundred ninety cases were classified as positive, including 143 cases of trisomy 21 and 47 cases of trisomy 18. With the karyotyping results and the feed back of fetal outcome data, we observed one false positive case of trisomy 21, one false positive case of trisomy 18 and no false negative cases, indicating 100% sensitivity and 99.96% specificity for the detection of trisomies 21 and 18. Conclusion Our large-scale multicenter study proved that the MPS-based test is of high sensitivity and specificity in detecting fetal trisomies 21 and 18. The introduction of this screening test into a routine clinical setting could avoid about 98% of invasive prenatal diagnostic procedures. © 2012 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this article.

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Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies

BackgroundConventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy.MethodsWe developed an advanced noninvasive prenatal diagnosis method based on massively parallel sequencing. The Noninvasive Fetal Trisomy (NIFTY) test, combines an optimized Student’s t-test with a locally weighted polynomial regression and binary hypotheses. We applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping.Results16 of 16 trisomy 21, 12 of 12 trisomy 18, two of two trisomy 13, three of four 45, X, one of one XYY and two of two XXY abnormalities were correctly identified. But one false positive case of trisomy 18 and one false negative case of 45, X were observed. The test performed with 100% sensitivity and 99.9% specificity for autosomal aneuploidies and 85.7% sensitivity and 99.9% specificity for sex chromosomal aneuploidies. Compared with three previously reported z-score approaches with/without GC-bias removal and with internal control, the NIFTY test was more accurate and robust for the detection of both autosomal and sex chromosomal aneuploidies in fetuses.ConclusionOur study demonstrates a powerful and reliable methodology for noninvasive prenatal diagnosis.

Clinical application of massively parallel sequencing‐based prenatal noninvasive fetal trisomy test for trisomies 21 and 18 in 11 105 pregnancies with mixed risk factors

To report the performance of massively parallel sequencing (MPS) based prenatal noninvasive fetal trisomy test based on cell-free DNA sequencing from maternal plasma in a routine clinical setting in China. The MPS-based test was offered as a prenatal screening test for trisomies 21 and 18 to pregnant women in 49 medical centers over 2 years. A total of 11,263 participants were recruited and the MPS-based test was performed in 11,105 pregnancies. Fetal outcome data were obtained after the expected date of confinement. One hundred ninety cases were classified as positive, including 143 cases of trisomy 21 and 47 cases of trisomy 18. With the karyotyping results and the feedback of fetal outcome data, we observed one false positive case of trisomy 21, one false positive case of trisomy 18 and no false negative cases, indicating 100% sensitivity and 99.96% specificity for the detection of trisomies 21 and 18. Our large-scale multicenter study proved that the MPS-based test is of high sensitivity and specificity in detecting fetal trisomies 21 and 18. The introduction of this screening test into a routine clinical setting could avoid about 98% of invasive prenatal diagnostic procedures.

Value of detection of cell-free fetal DNA in maternal plasma in the prenatal diagnosis of chromosomal abnormalities

To investigate the value of detection of fetal cell-free fetal DNA (cff-DNA) in maternal plasma in the prenatal diagnosis of chromosomal abnormalities. The plasma from 3200 gravidas (singleton with 20.3 ± 3.8 gestational weeks) was collected from April 1(st) 2011 to May 30(th) 2012. They were divided into 3 groups: (1) To tally 1720 cases were included in the high-risk serological screening group, in which women were younger than 35 years and got high-risk results in serological screening; (2) To tally 1310 cases were included in the advanced age group, in which women's age was more than 35 years; (3) To tally 170 cases were included in the supplementary group, in which women were younger than 35 years and got low-risk results in serological screening, or women who didn't take serological screening tests. All the 3030 gravidas in group 1 and 2 didn't take invasive prenatal diagnosis because of fear of abortion or short of prenatal diagnosis. Cff-DNA were detected by next generation sequencing in Shenzhen BGI Genomics Center for clinical laboratory. Amniocentesis and karyotype analysis were provided to the positive cases and women with negative results were followed-up by telephone. (1) The 3200 cases took cff-DNA detection, and 31 cases got positive results, including 27 cases of trisomy 21 and 4 cases of trisomy 18. Sixteen cases of trisomy 21 and 1 case of trisomy 18 were in the high-risk serological screening group. 7 cases of trisomy 21 and 2 cases of trisomy 18 were in the advanced age group. Four cases of trisomy 21 and 1 case of trisomy 18 were in the supplementary group. (2) And the 84% (26/31) cff-DNA detecting positive cases received amniocentesis. In the 27 trisomy 21 positive cases, 23 received amniocentesis and got karyotype of 47XN, +21, with the diagnostic accordance rate of 100%. In the 4 cases who didn't take karyotype analysis, fetal anomaly (ventricular septal defect, dextrocardia and choroid plexus cyst) was found in 1 case before 20 gestational weeks; intrauterine fetal demise happened in 1 case before getting the result; 2 other cases who already had healthy children took abortion in the local hospital without taking amniocentesis. In the 4 trisomy 18 positive cases, 3 took amniocentesis, 2 of which were trisomy 18 and took abortion, the other was chimera (46, XN/47, XN, +18) with only 2% cells of trisomy 18, with no malformation found after delivery. Hypoevolutism (3 weeks less than gestational week), general hydropsy and intrauterine fetal demise happened before the other case took amniocentesis. (3) Follow up of cff-DNA negative cases:until May 30(th) 2012, no Down's baby was found in the 1230 cases with cff-DNA test negative results. (1) The non-invasive fetal trisomy test (NIFTY) by next generation sequencing is a safe, accurate and high throughput method for the prenatal diagnosis of trisomy-21. (2) Use NIFTY as a further screening for pregnant women with high-risk serological screening results could lower invasive prenatal diagnosis rate. (3) Cases with positive NIFTY test results should receive amniocentesis and karyotype analysis to confirm the diagnosis before abortion.

Noninvasive prenatal genetic testing for fetal aneuploidy detects maternal trisomy X

Trisomy X is a sex chromosomal abnormality with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1000 female births. There is considerable variation in the phenotype, from asymptomatic and very mildly affected to significant physical and psychological features, leading only 10% of diagnosis ratio for those individuals with trisomy X. Current prenatal diagnosis of trisomy X relies on invasive prenatal tests such as karyotyping analysis. Although such tests allow accurate diagnosis, wide clinical use is limited by its complex operations and invasive nature with a 0.5% to 1% of procedure-related miscarriage. Recently, a newmethod based on massively parallel sequencing for cell-free DNA in maternal plasma was developed to detect fetal trisomy disorders. A rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis showed that the test currently available is only for fetal trisomy 21 and trisomy 18, which constitutes only about half of the fetal aneuploidy that would be identified through amniocentesis or CVS. Prior studies have shown that this massively parallel sequencing based noninvasive fetal trisomy test (the NIFTY test, which has no relationship with the ‘NIFTY’ trial on noninvasive prenatal diagnosis that was sponsored by the US National Institutes of Health) can not only detect trisomy 21 and trisomy 18, but also sex chromosomal aneuploidies. However, the effect of the maternal genetic background on the performance of the NIFTY test is not clear. Here we present a case in which maternal chromosome X materials affect the performance of the NIFTY. This case may provide a useful complement for the clinical application of the NIFTY test.

Clinical utility of noninvasive fetal trisomy (NIFTY) test – early experience

Objective: To report the initial experience of noninvasive prenatal diagnosis of fetal Down syndrome (The NIFTY test) in a clinical setting. Methods: The NIFTY test was offered as a screening test for fetal Down syndrome to pregnant women with a singleton pregnancy at 12 weeks of gestation or beyond. A satisfaction questionnaire was sent to the first 400 patients. Results: During a 6-month period, 567 NIFTY tests were performed. Over 90% of those studied were ethnic Chinese, and the mean age of the women studied was 36 years. The test was performed at 12–13 weeks of gestation in 49.21%. The median reporting time was 9 days. The test was positive for trisomy 21 in eight cases, and for trisomy 18 in 1 case; all were confirmed by fetal karyotyping. There was no false-positive result. Of the questionnaires, 182 completed responses were received. Over 95% had complete or almost complete resolution of anxiety. Except for one, all were satisfied with the NIFTY test, and all indicated that they would recommend the test to their friends. Conclusion: The NIFTY test was a highly specific test. Unnecessary invasive tests and associated fetal losses could be avoided in almost all women who have a normal fetus.