A prenatal case with discrepant findings between non-invasive prenatal testing and fetal genetic testings
© Pan et al.; licensee BioMed Central Ltd. 2014
Received: 14 March 2014
Accepted: 4 June 2014
Published: 16 July 2014
At 17+4 week, non-invasive prenatal testing (NIPT) results of a 24-years-old mother showed high risk of monosomy X (45, X). Abnormally shaped head and cardiac defects were observed in prenatal ultrasound scan at 19+3 week. Amniocentesis conducted at 19+3 week identified karyotype 47, XX, +18, which suggested that the NIPT failed to detect trisomy 18 (T18) in this case. With a further massively parallel sequencing (MPS) of maternal blood, fetal and placental tissues, we found a confined placental mosaicism (CPM) with non-mosaic T18 fetus and multiclonal placenta with high prevalence of 45, X and low level of T18 cells. FISH and SNP-array evidence from the placental tissue confirmed genetic discrepancy between the fetus and placenta. Because the primary source of the fetal cell-free DNA that NIPT assesses is mostly originated from trophoblast cells, the level of T18 placental mosaicism may cause false negative NIPT result in this rare case of double aneuploidy.
KeywordsNon-invasive prenatal testing Massively parallel sequencing Mosaicism
Non-invasive prenatal testing for common fetal aneuploidies, in particular trisomy 21 and 18, by massively parallel sequencing (MPS) of maternal plasma DNA is an extremely efficient screening test with sensitivity and specificity of over 99%.
Here we report a rare case with mosaic monosomy X and trisomy 18 in placenta, which induced a false negative NIPT result. Results of the 2nd trimester combined test (AFP 0.65 MoM and hCGb 4.32 MoM) indicated that the pregnancy of the 24-year-old mother (“gravida 2, para 0”, G2P0) was at high risk of Down syndrome (1/45). As the following screening, a NIPT test was then performed at 17+4 week of gestation by maternal peripheral blood collection, cell-free DNA (cfDNA) extraction, library construction and sequencing through Illumina HiSeq2000 platform.
To the contrary, G-banding, FISH and SNP-array analyses on the post-mortem fetal tissue all demonstrated positive results of complete T18, showing that the fetal tissue is genetically different from the placental tissue.
Analysis and conclusion
It is acknowledged that fetal cfDNA in maternal peripheral blood is originated from trophoblast and mainly consists of placental DNA[4, 5]. However, the genetic discordance between placental and fetal tissue may affect the NIPT test and lead to inaccurate results. False positive NIPT results, small but not negligible, have been reported and noted for concern in these years[6–8]. In addition, mosaic condition of placenta may reduce the measurement accuracy and cause false negative result. The present case offered strong evidence for the idea and was supported by a previous case of double trisomy in placenta. In this case, the fraction of fetal cfDNA for T18 caused by mosaic placenta is considerably lower than the detection threshold of NIPT test and consequently caused false negative results. Therefore, the level of mosaicism is an important factor for the NIPT test.
Collectively, considering the effect from placenta, the NIPT results should be interpreted combining other clinical tests under comprehensive background information.
Informed consent was obtained from the patient for publication of this case report and any accompanying images. The sample collection procedures are approved by Huai’an Maternal and Child Health Care Hospital Medical Ethics Committee.
Non-invasive prenatal testing
Massively parallel sequencing
Confined placental mosaicism
Fluorescence in situ hybridization
We thank the patient for participating in this study.This research was supported by the Major project in maternal and child health care,Jiangsu Province Department of Health of China (Grant no. F201214), and the Development Program for Technological Innovation and Platform Construction, HuaiAn City of China (Grant no. HAP201016).
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