Noninvasive prenatal testing for aneuploidy–ready for prime time?




Noninvasive prenatal diagnosis using cell-free fetal DNA in the maternal plasma is moving into routine clinical practice for some indications. Here we discuss exciting developments in noninvasive prenatal diagnosis for aneuploidy afforded by recent publications, including 2 papers published in this journal, and highlight some of the issues that need to be considered before these tests can be implemented as part of routine antenatal care.




See related articles, pages 319 and 322



Finally, after years of hunting for the elusive fetal cells in the maternal circulation to use for genetic prenatal diagnosis, it seems that cell-free fetal DNA (cffDNA) will provide the basis for a safer, noninvasive approach to prenatal diagnosis. Since the identification of cffDNA in maternal plasma in the late 1990s, there has been much research on how cffDNA can be used as an alternative to invasive tests to provide safer, yet robust, noninvasive prenatal diagnosis (NIPD) for families at high risk of genetic disorders and for other pregnancy complications such as hemolytic disease of the newborn and fetal aneuploidy. In recent months we have seen the publication of papers describing implementation of this technology into routine obstetric practice to direct administration of anti-D for all RhD-negative mothers and as part of standard genetic care to determine fetal sex for women at high risk of sex-linked disorders. The clinical utility of NIPD in reducing the need for invasive testing and favorable costs have been clearly demonstrated.


There have been a variety of approaches to the noninvasive diagnosis of aneuploidy reported ( Table 1 ), culminating in the recent publication of several validation projects demonstrating good sensitivities and specificities for the detection of trisomy 21 using next-generation sequencing. Such is the volume of work generated over recent years that we are now seeing the publication of systematic reviews describing the application of NIPD for both fetal sex determination and aneuploidy diagnosis. In this issue, we see 2 papers published describing an alternative sequencing approach to NIPD for aneuploidy that employs targeted, or chromosome-selective, sequencing that appears to be highly accurate and potentially more cost-effective than previously reported sequencing approaches.



TABLE 1

Summary of studies reporting detection of fetal aneuploidy using variety of methods of noninvasive prenatal diagnosis




























































































































































Study Method Total no. samples tested No. normal samples tested (true negatives) No. aneuploid samples tested (true positive) Sensitivity, % (95% CI) a Specificity, % (95% CI) a
Lo et al RNA allelic ratio 67 57 (55) 10 (9) 90 (60.6–99.5) 96.5 (89.4–99.4)
Tsui et al RNA allelic ratio 62 58 (51) 4 (4) 100 (47.3–100) 89.7 (80.6–95.4)
Fan et al MPS 18


  • T21 cohort: 9 (9)



  • T18 cohort: 16 (16)



  • T13 cohort: 17 (17)




  • T21: 9 (9)



  • T18: 2 (2)



  • T13: 1 (1)




  • T21: 100 (71.8–100)



  • T18: 100 (22.4–100)



  • T13: 100 (5–100)




  • T21: 100 (71.8–100)



  • T18: 100 (82.9–100)



  • T13: 100 (83.8–100)

Chiu et al MPS 28 14 (14) 14 (14) 100 (80.7–100) 100 (80.7–100)
Ghanta et al Tandem SNP 27 20 (20) 7 (7) 100 (65.2–100) 100 (86.1–100)
Tong et al Differential methylation 29 24 (23) 5 (5) 100 (55–100) 95.8 (81.7–99.8)
Papageorgiou et al Differential methylation 40 26 (26) 14 (14) 100 (80.7–100) 100 (89.2–100)
Deng et al RT-MLPA 113 87 (87) 25 (23) 92 (77–98.6) 100 (96.6–100)
Chiu et al MPS 15 10 (10) 5 (5) 100 (54.9–100) 100 (74.2–100)
Sehnert et al MPS 47


  • T21 cohort: 34 (34)



  • T18 cohort: 39 (39)



  • T13 cohort: 46 (46)




  • T21: 13 (13)



  • T18: 8 (8)



  • T13: 1 (no call)




  • T21: 100 (79.5–100)



  • T18: 100 (68.8–100)



  • T13: –




  • T21: 100 (91.6–100)



  • T18: 100 (92.6–100)



  • T13: 100 (93.7–100)

Chen et al MPS (2 plex) 289


  • T13 cohort: 264 (261)



  • T18 cohort: 252 (248)




  • T18: 37 (34)



  • T13: 25 (25)




  • T18: 91.9 (80.4–97.8)



  • T13: 100 (88.8–100)




  • T18: 98.9 (97.1–99.7)



  • T13: 98.4 (96.4–99.4)

Ehrich et al MPS (4 plex) 449 410 (409) 39 (39) 100 (92–100) 99.7 (98.8–99.9)
Lau et al MPS (12 plex) 108


  • T21 cohort: 97 (97)



  • T18 cohort: 98 (98)



  • T13 cohort: 106 (106)




  • T21: 11 (11)



  • T18: 10 (10)



  • T13: 2 (2)




  • T21: 100 (76.2–100)



  • T18: 100 (74.5–100)



  • T13: 100 (22.4–100)




  • T21: 100 (97–100)



  • T18: 100 (97–100)



  • T13: 100 (97.2–100)

Chiu et al MPS (8 plex) 657 571 (6) 86 (68) 79.1 (70.6–86) 98.9 (97.9–99.5)
Chiu et al MPS (2 plex) 232 146 (3) 86 (86) 100 (96.6–100) 97.9 (94.8–99.8)
Palomaki et al MPS 1683 1471 (1468) 212 (209) 98.6 (96.4–99.6) 99.8 (99.5–99.9)
Sparks et al Targeted MPS 167 123 (123)


  • T21: 36 (36)



  • T18: 8 (8)




  • T21: 100 (92.1–100)



  • T18: 100 (68.8–100)




  • T21: 100 (97.6–100)



  • T18: 100 (97.6–100)

Ashoor et al Targeted MPS 397 297 (297)


  • T21: 50 (50)



  • T18: 50 (49)




  • T21: 100 (94.2–100)



  • T18: 98 (90.1–99.9)




  • T21: 100 (99–100)



  • T18: 100 (99–100)

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May 23, 2017 | Posted by in GYNECOLOGY | Comments Off on Noninvasive prenatal testing for aneuploidy–ready for prime time?

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