Table 1: Survey of published cases of false negative NIPT by massive parallel shotgun sequencing with (molecular) cytogenetic follow-up included1.

TrisomyStudy [reference]Indication for NIPTCase,
mat. age
Blood drawn at GA2Fetal DNA fraction (effective fetal DNA fraction)Result of NIPTKaryotypeExplanation for false negative NIPT result

13Canick et al. (2013) [17]Ultrasound abnormalitiesCase  1
34 yrs
14 w6% (0.6%)-score 0.08 for chromosome 1346,XX/47,XX,+13 in cultured amniocytesAmniocentesis showed 10% mosaicism for a cell line with +13

18Canick et al. (2013) [17]Maternal ageCase  5
39 yrs
12 w23% (10%)-score 0.22 for chromosome 1847,XY,+21/48,XY,+18,+21 in CVSCVS showed 45% mosaicism for a cell line with both +18 and +21

18Gao et al. (2014) [25]1/70 risk for tri-21 by combined 1st trim. test43 yrs13 w7.4%Low risk tri-13,
tri-18, and tri-21, high risk XXX
48,XXX,+18 in cultured amniocytesEstimated 20–30% of placental cells studied by FISH were +18, with QF-PCR showing variable levels of +18 cells across the placenta

18Mao et al. (2014) [26]1/313 risk for tri-18 by serum screening22 yrs17 w11.6% (4.1%)-score 0.35 for tri-18; -score 4.4 for tri-2147,XX,+18 in cultured amniocytesPlacental biopsies showed on average 50% +21, 35% +18, and 15% normal cells, but at least one region had 61% +21 but only 22% +18

18Pan et al. (2014) [27]1/45 risk for tri-21 by combined test24 yrs18 wNot provided-score −0.52 for tri-18; -score −4.05 for X-chromosome47,XX,+18 in cultured amniocytes, both by karyotyping and SNP-arrayAbout 30% of placental cells studied by FISH were +18, and about 67% were 45, X; SNP-array was indicative of ~50% cells with +18

18Zhang et al. (2015) [28]1/360 risk for tri-21 by combined test29 yrs19 w5.3% (1.1–2.2%)Aneuploidy not detected47,XY,+18 in products of conception6 placental biopsies showed 20–40% cells with +18

18Zhang et al. (2015) [28]1/45 risk for tri-21 by combined test24 yrs20 w9.5% (2.9%)Indicative of 45,X47,XX,+18 in cultured amniocytesIn placental tissue 30% of the cells showed +18 and 60% showed 45,X

21Canick et al. (2013) [17]Maternal ageCase  2
44 yrs
11 w17% (1.7%)-score 2.03 for chromosome 21 46,XY20/47,XY,+212 in CVSCVS showed 9% mosaicism for a cell line with +21

21Canick et al. (2013) [17]Maternal ageCase  3
41 yrs
12 w9% (4.5%)-score −1.25 for chromosome 2146,XY/47,XY,+21 in CVS50% mosaicism by CVS; possibly this was lower in the placenta as a whole

21Wang et al. (2013) [29]1/370 risk for tri-21 by serum screening at 17 wCase  1
32 yrs
18 w15.6%-score 2.043 for chromosome 2146,XX,der(21;21)(q10;q10),+21 in fetal blood (cordocentesis)Placental biopsies had 17%, 21%, 23%, and 53% cells with +21

21Wang et al. (2013) [29]2 spontaneous abortionsCase  2
35 yrs
18 w19.7%-score 1.33 for chromosome 2147,XY,+21 in cultured amniocytesPlacental biopsies had 2%, 51%, and 76% cells with +21

21Smith et al. (2014) [30]CAVCD432 yrs20 wNot provided“Negative” for trisomy 2147,XX,+21 in postnatal bloodNo study of placenta or umbilical cord; no explanation provided

Notes. 1A false negative case of trisomy 21 was also mentioned by Wang et al. [31], 2 other false negative trisomy 21 cases were mentioned by Dar et al. [32], and another 6 false negative trisomy 21 cases were described by Zhang et al. [28]; a false negative case of trisomy 18 was mentioned by Beamon et al. [33], another one by Quezada et al. [34] and by Zhang et al. [28]; 3 false negative cases of tri-13 were reported by Quezada et al. [34]; all of these were without further investigation of the possible causes of the discrepant findings.
2GA: gestational age.
3In a repeat blood sample taken at 24 weeks the -score for chromosome 21 was 4.0 and trisomy-21 was reported as a result.
4CAVCD: complete atrioventricular canal defect.