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Causes of false positive NIPT
October-November was a busy month with lots of congresses relevant to our field. I had the pleasure to be invited to the Inaugural International congress for Reproductive Genetics in Beijing where I enjoyed the hospitality of my Chinese hosts Jie Qiao and Siaoliang Sunney Xie. The meeting brings together basic scientists and clinicians in the growing field of reproductive genetics, the crossroads of genetic causes of infertility, embryonic genetics typically performed in fertility centers and prenatal genetic care. It is fabulous to see how China is moving forward with research on non-invasive prenatal testing. I marked next year’s meeting in my calendar which will take place in October in Macau. November 7-9, I enjoyed in Paris the 6th world congress on Controversies in Genetics jointly with the fourteenth Ovarian club meeting. The often-heated debates on the hot topics, amongst which NIPT, were attended by over 400 colleagues. If no plans yet, mark November 5-7 in your agenda to join me for the 2020 edition under the lights of the Eifel Tower.
One of the topics on the agenda of those meetings were the causes of false positives following non-invasive prenatal testing (NIPT). As discussed in the previous newsletter, all positive NIPTs should be confirmed by an invasive prenatal genetic test. Why do false positive results occur during NIPT? First of all, the different NIPT tests on the market have different underlying technologies each with slightly different accuracies. However, it seems likely that technical causes make only a minor fraction of the false positives. The major cause for false positive results appears to have a biological origin. I will here elaborate on the main reasons.
The main reason for false positives and false negative results is the existence of placental mosaicism. The main source of circulating cell free fetal DNA has been shown to be of placental origin. It is well documented from the conventional cytogenetic examination of Chorion villus tissue (CVS) that confined placental mosaicism occurs in which the placental tissue contains an abnormal cell line that is not present upon subsequent examination of amniocentesis or other fetal material. This CPM is observed in around 1% of invasive tests. A second reason for discrepancies between NIPT and invasive genetic testing is the presence of a ‘vanishing twin’. The placentas of both dizygotic twins shed DNA in the maternal bloodstream. However, sometimes one member of the twin demises. The remnants of placenta are still present and contribute to the NIPT signal. The theoretical incidence of a vanishing twin with a chromosome abnormality is estimated to be around 0.11%. This emphasizes the importance of detailed ultrasound examination, particularly following discordant NIPT results.
NIPT relies upon the analysis of cell free DNA derived from the maternal plasma, and the majority, 80-95% of this circulating DNA is not derived from the placenta but is of maternal origin. Any variation in the genetic constitution compared to the normal can skew the results. Each of us is carrying copy number variations, chunks of DNA which can be present in more or less copies compared to the general population. Occasionally this variation interferes with the NIPT tests. Also, if a pregnant woman has a tumor, this can interfere with the NIPT. Tumors behave like placentas: blood veins provide oxygen to the tumor tissue and degrading tumor tissue is released in the blood stream. The more advanced a tumor is, the more tumor DNA can be detected in the cfDNA. Since the majority of tumors are characterized by large segments of DNA carrying copy number variation, those variants can interfere with the NIPT. Consequently, if a pregnant woman with a tumor or a hematological malignancy presents for NIPT, this would be a counter indication and the NIPT should not be offered. Finally, tissue transplants can confound the results as well. Those conditions should be mentioned, when requesting NIPT.