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NIPT For Microdeletions – how useful is it?

Non-invasive prenatal testing (NIPT) is a test widely prescribed to all pregnant women (Liehr et al., 2017) especially to women with high-risk pregnancy (advanced maternal age, history of spontaneous miscarriages, family history of genetic abnormalities or unhealthy lifestyle). This test screens the fetal cell free DNA extracted from maternal blood for underlying chromosomal abnormalities like trisomies 13, 18 and 21. Any positive test is later confirmed by karyotyping and/FISH using invasive procedures for sampling like amniocentesis or CVS. This test helps reduce the number of invasive procedures and can be very reassuring for routine/low risk cases.

NIPT – very high sensitivity of Trisomy 21

NIPT can screen trisomy 21 with accuracy rate as high as 99% (Carlson and Vora, 2017). Other abnormalities like trisomy 13 and 18, neural tube defects and sex chromosome defects can also be screened with high accuracy using NIPT.

Given the utility of NIPT in screening of fetuses for genetic abnormalities, there are assays which have expanded the scope of NIPT to include other relatively rarer conditions and microdeletions. The idea was to make the assay more comprehensive and provide a greater assurance to the expecting parents.

NIPT for microdeletions – more false positives

Many recent research studies have pointed out that the inclusion of other rare autosomal trisomies or microdeletions using NIPT is questionable as it increases the false positivity rate (Jani et al., 2020).

A study carried out by Luthgens and team (Cenata GmbH) reported that only 5.4% of 147 NIPT positive cases of DiGeorge’s syndrome (Harmony platform) were true positives while the true positivity rate for other trisomies like 13, 18 and 21 was very high (“News_02-2022_Cenata GmbH_Harmony (1).pdf,” n.d.)

The false positives raise the anxiety levels amongst the patients and in some circumstances, may result into unnecessary abortion. People might be in continuous fear of delivering an abnormal baby even if the fetal karyotype is proven to be normal after positive NIPT results. Benn et al in 2019 reported that the clinical outcome of cases with positive NIPT test resulted in the birth of a normal baby (40%) or a miscarriage/fetal loss (27%), for which screening tests were not recommended (Benn et al., 2019; Jani et al., 2020). There was found to be a weak association between RATs and pregnancy complications.

It is evident from the above-mentioned analysis that NIPT can be recommended for the screening of common trisomy (13, 18 and 21) and sex chromosome defects but its sensitivity for screening of microdeletions is highly compromised. Therefore, it becomes a moral responsibility of diagnostics centres and clinicians not to make false commitments to the patients and put them in dilemma which may end them up in undergoing the invasive procedures for NIPT test confirmation or even taking wrong decisions for pregnancy termination.

References:

Benn, P., Malvestiti, F., Grimi, B., Maggi, F., Simoni, G., Grati, F.R., 2019. Rare autosomal trisomies: comparison of detection through cell‐free DNA analysis and direct chromosome preparation of chorionic villus samples. Ultrasound Obstet Gynecol 54, 458–467. https://doi.org/10.1002/uog.20383

Carlson, L.M., Vora, N.L., 2017. Prenatal Diagnosis. Obstetrics and Gynecology Clinics of North America 44, 245–256. https://doi.org/10.1016/j.ogc.2017.02.004

Jani, J.C., Gil, M.M., Benachi, A., Prefumo, F., Kagan, K.O., Tabor, A., Bilardo, C.M., Di Renzo, G.C., Nicolaides, K.H., 2020. Genome‐wide cfDNA testing of maternal blood. Ultrasound Obstet Gynecol 55, 13–14.
https://doi.org/10.1002/uog.21945

Liehr, T., Lauten, A., Schneider, U., Schleussner, E., Weise, A., 2017. Noninvasive Prenatal Testing – When Is It Advantageous to Apply. Biomed Hub 2, 1–11.
https://doi.org/10.1159/000458432

News_02-2022_Cenata GmbH_Harmony (1).pdf, n.d.

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