Almighty NIPT: Discussion of limitations
Ming Chen, MD, PhD
Changhua Christian Hospital, and National Taiwan University
Non-invasive prenatal testing/screening (NIPT/NIPS) becomes popular recently. The introduction of this test has profound impact upon the landscape of prenatal genetics and fetal medicine. With an extremely high sensitivity/specificity to common human fetal trisomies including trisomy 21, 18, and 13 noted in the published results, some myths need to be clarified before we really know it well. It is mighty (powerful), but not almighty (without limitations). As the team leader of the very few Taiwanese labs trying to develop our own platform and system, the speaker feels the urge to discuss first the limitations of NIPT, instead of promoting its power.
Published methodologies of cell-free NIPT assays included shotgun sequencing, targeted sequencing (including SNP), and methylation-related immunoprecipitation (MeDIP). Errors can arise from each step of experiments and bioinformatics analyses adopted, therefore appropriate accreditation are mandatory. It is unfortunate possible fair accreditation is hampered by commercialization because of the filed patent (even in US). Each company regards those steps vitally affecting the accuracy of the results as protected intellectual property. Moreover, even the test was offered from well-recognized service providers such as Sequenom, the clinicians need to be aware of the following limitations: the fraction of fetal DNA (which is greatly affected by parameters like gestational age and maternal weight at blood withdrawn), multiple pregnancy, and the not-so-uncommon confined placental mosaicism.
NIPT/NIPS is no doubt far more superior to current non-invasive screening methods based upon ultrasound and serum biochemical markers if regarding the risk estimation of fetal trisomy 21, 18, 13. However, its resolution at the moment, is far less than the genetics tools available which invasive tests can offer. The sporadic reports (despite in prestigious journals) of using NIPD to diagnose microdeletion syndromes or even monogenic inherited disorders demanded a very high sequencing depth. Lastly, it has been shown counting algorithm can affect the accuracy of the NIPT/NIPS and most of the counting algorithms published are protected by the filed patents in US. The booming of NIPT business in the Greater China region actually is not followed by any published validity results and the algorithms they used in detail are kept confidential. Clinicians and healthcare providers need to be caution when applying these tests.
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