Noninvasive prenatal testing

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Noninvasive prenatal testing
Other namesNIPT
Specialty Medical diagnosis, obstetrics and gynaecology

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]

Background

The use of ultrasound and biochemical markers to detect aneuploidies is usually done in the first and / or second trimester of pregnancy. However, both of these approaches have a high rate of false positive results of 2–7%. [6] 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%. [7] 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. [8]

Circulating cffDNA can be detected in maternal blood between the 5th and the 7th week of gestational age, [9] however more fetal DNA is available for analysis usually after 10 weeks, because the amount of fetal DNA increases over time. [10] 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. [11] [12] [13] [14]

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). [15] [16] [17] 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. [18] 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. [19]

NIPT can determine paternity and fetal sex earlier in gestation than previous tests (including possibly ultrasound). [20] It is also used to determine fetal Rhesus D, which can prevent mothers who are Rhesus D negative from undergoing unnecessary prophylactic treatment. [21] [22] 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. [8]

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. [23] 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. [24] [25]

Related Research Articles

<span class="mw-page-title-main">Down syndrome</span> Genetic disorder

Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with developmental delays, mild to moderate intellectual disability, and characteristic physical features. There are three types of Down syndrome, all with the same features: Trisomy 21, the most common type; Mosaic Down syndrome, and Translocation Down syndrome.

<span class="mw-page-title-main">Amniocentesis</span> Sampling of amniotic fluid done mainly to detect fetal chromosomal abnormalities

Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is necessary to conclusively diagnose the majority of genetic disorders, with amniocentesis being the gold-standard procedure after 15 weeks' gestation.

<span class="mw-page-title-main">Prenatal testing</span> Testing for diseases or conditions in a fetus

Prenatal testing is a tool that can be used to detect some birth defects at various stages prior to birth. Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of the zygote, embryo, or fetus, either before gestation even starts or as early in gestation as practicable. Screening can detect problems such as neural tube defects, chromosome abnormalities, and gene mutations that would lead to genetic disorders and birth defects, such as spina bifida, cleft palate, Down syndrome, trisomy 18, Tay–Sachs disease, sickle cell anemia, thalassemia, cystic fibrosis, muscular dystrophy, and fragile X syndrome. Some tests are designed to discover problems which primarily affect the health of the mother, such as PAPP-A to detect pre-eclampsia or glucose tolerance tests to diagnose gestational diabetes. Screening can also detect anatomical defects such as hydrocephalus, anencephaly, heart defects, and amniotic band syndrome.

<span class="mw-page-title-main">Chorionic villus sampling</span> Type of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus

Chorionic villus sampling (CVS), sometimes called "chorionic villous sampling", is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it for chromosomal abnormalities, usually with FISH or PCR. CVS usually takes place at 10–12 weeks' gestation, earlier than amniocentesis or percutaneous umbilical cord blood sampling. It is the preferred technique before 15 weeks.

<span class="mw-page-title-main">Choroid plexus cyst</span> Medical condition

Choroid plexus cysts (CPCs) are cysts that occur within choroid plexus of the brain. They are the most common type of intraventricular cyst, occurring in 1% of all pregnancies.

The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy in the second trimester to classify a patient as either high-risk or low-risk for chromosomal abnormalities.

<span class="mw-page-title-main">Polysomy</span> Abnormal multiples of one or more chromosomes

Polysomy is a condition found in many species, including fungi, plants, insects, and mammals, in which an organism has at least one more chromosome than normal, i.e., there may be three or more copies of the chromosome rather than the expected two copies. Most eukaryotic species are diploid, meaning they have two sets of chromosomes, whereas prokaryotes are haploid, containing a single chromosome in each cell. Aneuploids possess chromosome numbers that are not exact multiples of the haploid number and polysomy is a type of aneuploidy. A karyotype is the set of chromosomes in an organism and the suffix -somy is used to name aneuploid karyotypes. This is not to be confused with the suffix -ploidy, referring to the number of complete sets of chromosomes.

The Pallister–Killian syndrome (PKS), also termed tetrasomy 12p mosaicism or the Pallister mosaic aneuploidy syndrome, is an extremely rare and severe genetic disorder. PKS is due to the presence of an extra and abnormal chromosome termed a small supernumerary marker chromosome (sSMC). sSMCs contain copies of genetic material from parts of virtually any other chromosome and, depending on the genetic material they carry, can cause various genetic disorders and neoplasms. The sSMC in PKS consists of multiple copies of the short arm of chromosome 12. Consequently, the multiple copies of the genetic material in the sSMC plus the two copies of this genetic material in the two normal chromosome 12's are overexpressed and thereby cause the syndrome. Due to a form of genetic mosaicism, however, individuals with PKS differ in the tissue distributions of their sSMC and therefore show different syndrome-related birth defects and disease severities. For example, individuals with the sSMC in their heart tissue are likely to have cardiac structural abnormalities while those without this sSMC localization have a structurally normal heart.

<span class="mw-page-title-main">Nuchal scan</span> Routine ultrasound done between 11 and 14 weeks pregnancy

A nuchal scan or nuchal translucency (NT) scan/procedure is a sonographic prenatal screening scan (ultrasound) to detect chromosomal abnormalities in a fetus, though altered extracellular matrix composition and limited lymphatic drainage can also be detected.

Noninvasive genotyping is a modern technique for obtaining DNA for genotyping that is characterized by the indirect sampling of specimen, not requiring harm to, handling of, or even the presence of the organism of interest. Beginning in the early 1990s, with the advent of PCR, researchers have been able to obtain high-quality DNA samples from small quantities of hair, feathers, scales, or excrement. These noninvasive samples are an improvement over older allozyme and DNA sampling techniques that often required larger samples of tissue or the destruction of the studied organism. Noninvasive genotyping is widely utilized in conservation efforts, where capture and sampling may be difficult or disruptive to behavior. Additionally, in medicine, this technique is being applied in humans for the diagnosis of genetic disease and early detection of tumors. In this context, invasivity takes on a separate definition where noninvasive sampling also includes simple blood samples.

The genetics and abortion issue is an extension of the abortion debate and the disability rights movement. Since the advent of forms of prenatal diagnosis, such as amniocentesis and ultrasound, it has become possible to detect the presence of congenital disorders in the fetus before birth. Specifically, disability-selective abortion is the abortion of fetuses that are found to have non-fatal mental or physical defects detected through prenatal testing. Many prenatal tests are now considered routine, such as testing for Down syndrome. Women who are discovered to be carrying fetuses with disabilities are often faced with the decision of whether to abort or to prepare to parent a child with disabilities.

<span class="mw-page-title-main">Trisomy 16</span> Partial or complete triplication of chromosome 16

Trisomy 16 is a chromosomal abnormality in which there are 3 copies of chromosome 16 rather than two. It is the most common trisomy leading to miscarriage and the second most common chromosomal cause of it, closely following X-chromosome monosomy. About 6% of miscarriages have trisomy 16. Those mostly occur between 8 and 15 weeks after the last menstrual period.

Sequenom, Inc. is an American company based in San Diego, California. It develops enabling molecular technologies, and highly sensitive laboratory genetic tests for NIPT. Sequenom's wholly owned subsidiary, Sequenom Center for Molecular Medicine (SCMM), offers multiple clinical molecular genetics tests to patients, including MaterniT21, plus a noninvasive prenatal test for trisomy 21, trisomy 18, and trisomy 13, and the SensiGene RHD Fetal RHD genotyping test.

Ravinder (Rav) Dhallan is the chairman and chief executive officer of Ravgen.

Natera, Inc. is a clinical genetic testing company based in Austin, Texas that specializes in non-invasive, cell-free DNA (cfDNA) testing technology, with a focus on women’s health, cancer, and organ health. Natera’s proprietary technology combines novel molecular biology techniques with a suite of bioinformatics software that allows detection down to a single molecule in a tube of blood. Natera operates CAP-accredited laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) in San Carlos, California and Austin, Texas.

Cell-free fetal DNA (cffDNA) is fetal DNA that circulates freely in the maternal blood. Maternal blood is sampled by venipuncture. Analysis of cffDNA is a method of non-invasive prenatal diagnosis frequently ordered for pregnant women of advanced maternal age. Two hours after delivery, cffDNA is no longer detectable in maternal blood.

<span class="mw-page-title-main">Diana W. Bianchi</span> American medical geneticist and neonatologist

Diana W. Bianchi is the director of the U.S. National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development, a post often called “the nation’s pediatrician.” She is a medical geneticist and neonatologist noted for her research on fetal cell microchimerism and prenatal testing. Bianchi had previously been the Natalie V. Zucker Professor of Pediatrics, Obstetrics, and Gynecology at Tufts University School of Medicine and founder and executive director of the Mother Infant Research Institute at Tufts Medical Center. She also has served as Vice Chair for Research in the Department of Pediatrics at the Floating Hospital for Children at Tufts Medical Center.

<span class="mw-page-title-main">Trisomy X</span> Chromosome disorder in women

Trisomy X, also known as triple X syndrome and characterized by the karyotype 47,XXX, is a chromosome disorder in which a female has an extra copy of the X chromosome. It is relatively common and occurs in 1 in 1,000 females, but is rarely diagnosed; fewer than 10% of those with the condition know they have it.

Beryl Rice Benacerraf was an American radiologist and professor of obstetrics, gynecology and reproductive biology and radiology at Harvard Medical School. She was a pioneer in the use of prenatal ultrasound to diagnose fetal abnormalities, including Down syndrome. In 2021, she was recognized as a "Giant in Obstetrics and Gynecology" by the American Journal of Obstetrics & Gynecology.

Dame Lyn Susan Chitty is a British physician and Professor of Genetics and Fetal Medicine at University College London. She is the deputy director of the National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre. She is the 2022 president of the International Society for Prenatal Diagnosis. Her research considers non-invasive prenatal diagnostics. She was made a Dame in the 2022 New Year Honours.

References

  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.
  4. ↑ Skrzypek, Hannah; Hui, Lisa (2017-07-01). "Noninvasive prenatal testing for fetal aneuploidy and single gene disorders". Best Practice & Research Clinical Obstetrics & Gynaecology. 42: 26–38. doi:10.1016/j.bpobgyn.2017.02.007. ISSN   1521-6934. PMID   28342726.
  5. ↑ "What is noninvasive prenatal testing (NIPT) and what disorders can it screen for?: MedlinePlus Genetics". medlineplus.gov. Retrieved 2021-06-27.
  6. ↑ Shamshirsaz, Alireza A.; Benn, Peter; Egan, James F.X. (2010-09-01). "The Role of Second-Trimester Serum Screening in the Post–First-Trimester Screening Era". Clinics in Laboratory Medicine. 30 (3): 667–676. doi:10.1016/j.cll.2010.04.013. ISSN   0272-2712. PMID   20638580.
  7. ↑ Amniocentesis and Chorionic Villus Sampling (Green-top Guideline No. 8) rcog.org.uk 25 October 2021 Retrieved 30 March 2023
  8. 1 2 Allyse, Megan; Minear, Mollie A.; Berson, Elisa; Sridhar, Shilpa; Rote, Margaret; Hung, Anthony; Chandrasekharan, Subhashini (2015-01-16). "Non-invasive prenatal testing: a review of international implementation and challenges". International Journal of Women's Health. 7: 113–126. doi: 10.2147/IJWH.S67124 . PMC   4303457 . PMID   25653560.
  9. ↑ Wright, Caroline F.; Burton, Hilary (2009). "The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal diagnosis". Human Reproduction Update. 15 (1): 139–151. doi: 10.1093/humupd/dmn047 . ISSN   1460-2369. PMID   18945714.
  10. ↑ Chiu, Rossa W. K.; Lo, Y. M. Dennis (2011-04-01). "Non-invasive prenatal diagnosis by fetal nucleic acid analysis in maternal plasma: the coming of age". Seminars in Fetal and Neonatal Medicine. 16 (2): 88–93. doi:10.1016/j.siny.2010.10.003. ISSN   1744-165X. PMID   21075065.
  11. ↑ Sayres, Lauren C.; Cho, Mildred K. (2011). "Cell-Free Fetal Nucleic Acid Testing: A Review of the Technology and Its Applications". Obstetrical & Gynecological Survey. 66 (7): 431–442. doi:10.1097/OGX.0b013e31822dfbe2. ISSN   0029-7828. PMID   21944155. S2CID   17018886.
  12. ↑ Hall, A.; Bostanci, A.; Wright, C. F. (2010). "Non-Invasive Prenatal Diagnosis Using Cell-Free Fetal DNA Technology: Applications and Implications". Public Health Genomics. 13 (4): 246–255. doi:10.1159/000279626. ISSN   1662-4246. PMID   20395693. S2CID   26020661.
  13. ↑ Hung, E. C. W.; Chiu, R. W. K.; Lo, Y. M. D. (2009-04-01). "Detection of circulating fetal nucleic acids: a review of methods and applications". Journal of Clinical Pathology. 62 (4): 308–313. doi:10.1136/jcp.2007.048470. ISSN   0021-9746. PMID   19329710. S2CID   21367768.
  14. ↑ Lo, Y. M. D. (2009). "Noninvasive prenatal detection of fetal chromosomal aneuploidies by maternal plasma nucleic acid analysis: a review of the current state of the art". BJOG: An International Journal of Obstetrics & Gynaecology. 116 (2): 152–157. doi:10.1111/j.1471-0528.2008.02010.x. ISSN   1471-0528. PMID   19076946. S2CID   6946087.
  15. ↑ Nicolaides, Kypros H.; Syngelaki, Argyro; Ashoor, Ghalia; Birdir, Cahit; Touzet, Gisele (2012-11-01). "Noninvasive prenatal testing for fetal trisomies in a routinely screened first-trimester population". American Journal of Obstetrics & Gynecology. 207 (5): 374.e1–374.e6. doi:10.1016/j.ajog.2012.08.033. ISSN   0002-9378. PMID   23107079.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ "Enforcement Notice - Advertising Non-invasive Prenatal Testing".
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ <https://www.natera.com/resource-library/publications/smart-22q-1-2022-fully-published
  24. ↑ 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.
  25. ↑ "Panorama Overview V4".
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