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Noninvasive prenatal testing

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Noninvasive prenatal testing (NIPT) is a method used to determine the risk for the fetus being born with certain chromosomal abnormalities, such as trisomy 21, trisomy 18 and trisomy 13.[1][2][3] This testing analyzes small DNA fragments that circulate in the blood of a pregnant woman.[4] Unlike most DNA found in the nucleus of a cell, these fragments are not found within the cells, instead they are free-floating, and so are called cell free fetal DNA (cffDNA). These fragments usually contain less than 200 DNA building blocks (base pairs) and arise when cells die, and their contents, including DNA, are released into the bloodstream. cffDNA derives from placental cells and is usually identical to fetal DNA. Analysis of cffDNA from placenta provides the opportunity for early detection of certain chromosomal abnormalities without harming the fetus.[5]

Noninvasive prenatal testing
Other namesNIPT
SpecialtyMedical diagnosis, obstetrics and gynaecology

Background

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The use of ultrasound and biochemical markers to detect aneuploidies is usually done in the first and / or second trimester of pregnancy. [6]Aneuploidies is when a fetus retains an abnormal amount of haploid cells from their parents. However, both of these approaches have a high rate of false positive results of 2–7%.[7] If these tests indicate an increased risk of aneuploidy, then invasive diagnostic testing is used, such as amniocentesis or chorionic villus sampling. Many women, however, feel uncomfortable with the invasive testing, because of the risk associated with miscarriage, which is around 0.5%.[8] Noninvasive prenatal testing is an intermediate step between prenatal screening and invasive diagnostic testing. The only physical risk associated with the procedure is the blood draw and there is no risk of miscarriage.[9]

Circulating cffDNA can be detected in maternal blood between the 5th and the 7th week of gestational age,[10] however more fetal DNA is available for analysis usually after 10 weeks, because the amount of fetal DNA increases over time.[11] cffDNA, RNA and intact fetal cells can all be used to assess the genetic status of the fetus non-invasively. Recent advances in DNA sequencing, such as massive parallel sequencing (MPS) and digital polymerase chain reaction (PCR), are currently under exploration for the detection of chromosomal aneuploidies via NIPT/NIPS.[12][13][14][15]

Since 2014, noninvasive testing has identified aneuploidies in chromosomes 13, 16, 18, 21, 22, X and Y, including Down syndrome (caused by trisomy 21), Edwards syndrome (caused by trisomy 18), Patau syndrome (caused by trisomy 13), as well as sex chromosome aneuploidies, such as Turner syndrome (45, X) and Klinefelter syndrome (47, XXY).[16][17][18] These methods of cffDNA sequencing have sensitivity and specificity rates greater than 99% in identifying Trisomy 21. Sensitivity and specificity rates are lower for other aneuploidies, such as trisomy 18 (97–99% and > 99%, respectively), trisomy 13 (87–99% and > 99%, respectively), and 45, X (92–95% and 99%, respectively). The low false positive rate (1–3%) is one of the advantages of NIPT which allows pregnant women to avoid invasive procedures.[19] In the UK the Advertising Standards Authority has stated that one should not quote “Detection Rate” figures unless the figures are accompanied by (i.e. alongside)a robust "Positive Predictive Value" figure; and a clear explanations about what both figures mean.[20]

NIPT can determine paternity and fetal sex earlier in gestation than previous tests (including possibly ultrasound).[21] It is also used to determine fetal Rhesus D, which can prevent mothers who are Rhesus D negative from undergoing unnecessary prophylactic treatment.[22][23] Finally, it is used to detect genetic mutations, such as duplications or microdeletions, including 1p, 5p, 15q, 22q, 11q, 8q, and 4p. The sensitivity and specificity of these tests, however, for most have not yet been validated.[9]

The Natera SMART study however has shown that most cases of 22q11.2 deletion can be detected using SNP based NIPT/NIPS (Panorama) including smaller nested deletions whilst still maintaining a low false positive rate.[24] Single nucleotide polymorphism (SNP) NIPT can also detect Triploidy and can differentiate between maternal and "fetal" DNA which reduces the redraw rate and allows determination of gender for each fetus in twin pregnancies and can be done from 9 weeks of pregnancy.[25][26]

For micro deletions such as DiGeorge syndrome, 1p36 deletion, Cri-du-chat syndrome, Wolf-Hirschhorn syndrome, Prader-Willi and Angelman syndromes, positive results can be incorrect as much as 85% of the time, according to a New York Times investigation.[27]

References

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  1. ^ Dondorp, Wybo; de Wert, Guido; Bombard, Yvonne; Bianchi, Diana W.; Bergmann, Carsten; Borry, Pascal; Chitty, Lyn S.; Fellmann, Florence; Forzano, Francesca; Hall, Alison; Henneman, Lidewij (2015). "Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening". European Journal of Human Genetics. 23 (11): 1438–1450. doi:10.1038/ejhg.2015.57. ISSN 1476-5438. PMC 4613463. PMID 25782669.
  2. ^ Goldwaser, Tamar; Klugman, Susan (2018). "Cell-free DNA for the detection of fetal aneuploidy". Fertility and Sterility. 109 (2): 195–200. doi:10.1016/j.fertnstert.2017.12.019. ISSN 0015-0282. PMID 29447662.
  3. ^ Rose, Nancy C.; Kaimal, Anjali J.; Dugoff, Lorraine; Norton, Mary E.; Medicin, American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins-ObstetricsCommittee on GeneticsSociety for Maternal-Fetal (2020). "Screening for Fetal Chromosomal Abnormalities: ACOG Practice Bulletin, Number 226". Obstetrics & Gynecology. 136 (4): e48–e69. doi:10.1097/AOG.0000000000004084. ISSN 0029-7844. PMID 32804883.
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  17. ^ Zimmermann, Bernhard; Hill, Matthew; Gemelos, George; Demko, Zachary; Banjevic, Milena; Baner, Johan; Ryan, Allison; Sigurjonsson, Styrmir; Chopra, Nikhil; Dodd, Michael; Levy, Brynn (2012). "Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci". Prenatal Diagnosis. 32 (13): 1233–1241. doi:10.1002/pd.3993. ISSN 1097-0223. PMC 3548605. PMID 23108718.
  18. ^ Palomaki, Glenn E.; Deciu, Cosmin; Kloza, Edward M.; Lambert-Messerlian, Geralyn M.; Haddow, James E.; Neveux, Louis M.; Ehrich, Mathias; van den Boom, Dirk; Bombard, Allan T.; Grody, Wayne W.; Nelson, Stanley F. (2012). "DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study". Genetics in Medicine. 14 (3): 296–305. doi:10.1038/gim.2011.73. ISSN 1530-0366. PMC 3938175. PMID 22281937.
  19. ^ Dickens, Bernard M. (2014). "Ethical and legal aspects of noninvasive prenatal genetic diagnosis". International Journal of Gynecology & Obstetrics. 124 (2): 181–184. doi:10.1016/j.ijgo.2013.11.001. ISSN 1879-3479. PMID 24299974. S2CID 29627343.
  20. ^ "Enforcement Notice - Advertising Non-invasive Prenatal Testing".
  21. ^ Devaney, Stephanie A.; Palomaki, Glenn E.; Scott, Joan A.; Bianchi, Diana W. (2011-08-10). "Noninvasive Fetal Sex Determination Using Cell-Free Fetal DNA: A Systematic Review and Meta-analysis". JAMA. 306 (6): 627–636. doi:10.1001/jama.2011.1114. ISSN 0098-7484. PMC 4526182. PMID 21828326.
  22. ^ Goodspeed, Taylor A.; Allyse, Megan; Sayres, Lauren C.; Norton, Mary E.; Cho, Mildred K. (2013-01-01). "Translating cell-free fetal DNA technology: structural lessons from non-invasive RhD blood typing". Trends in Biotechnology. 31 (1): 7–9. doi:10.1016/j.tibtech.2012.09.001. ISSN 0167-7799. PMC 6309969. PMID 23040170.
  23. ^ Clausen, Frederik Banch (2014). "Integration of noninvasive prenatal prediction of fetal blood group into clinical prenatal care". Prenatal Diagnosis. 34 (5): 409–415. doi:10.1002/pd.4326. ISSN 1097-0223. PMID 24431264. S2CID 222098536.
  24. ^ <https://www.natera.com/resource-library/publications/smart-22q-1-2022-fully-published
  25. ^ Dar, P.; Jacobsson, B.; MacPherson, C.; Egbert, M.; Malone, F.; Wapner, R. J.; Roman, A. S.; Khalil, A.; Faro, R.; Madankumar, R.; Edwards, L.; Haeri, S.; Silver, R.; Vohra, N.; Hyett, J.; Clunie, G.; Demko, Z.; Martin, K.; Rabinowitz, M.; Flood, K.; Carlsson, Y.; Doulaveris, G.; Malone, C.; Hallingstrom, M.; Klugman, S.; Clifton, R.; Kao, C.; Hakonarson, H.; Norton, M. E. (2022). "Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation". American Journal of Obstetrics and Gynecology. 227 (2): 259.e1–259.e14. doi:10.1016/j.ajog.2022.01.019. PMID 35085538. S2CID 246331398.
  26. ^ "Panorama Overview V4".
  27. ^ Kliff, Sarah; Bhatia, Aatish (January 1, 2022). "When They Warn of Rare Disorders, These Prenatal Tests Are Usually Wrong". The New York Times. Retrieved 18 August 2024.
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