DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations

Canick, Jacob A.; Kloza, Edward M.; Lambert-Messerlian, Geralyn; Haddow, James E.; Ehrich, Mathias; Boom, Dirk van den; Bombard, Allan T.; Deciu, Cosmin; Palomaki, Glenn E.

doi:10.1002/pd.3892

Cited by 158 publications

(170 citation statements)

References 13 publications

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“…Although the total fetal fraction of twin pregnancies might be higher than that of singletons10, the individual contribution from each twin is generally lower than that of a singleton8, 9; however, there may be exceptions. In our study, the average combined fetal fraction of both twins (16.1%) was higher than determined previously for singletons over similar gestational‐age ranges (12.6%; P = 0.001)21, and higher still than the average fetal fraction for a single twin (7.8%; P < 0.0001), consistent with the previously mentioned studies.…”

Section: Discussionmentioning

confidence: 94%

“…Traditionally, prenatal aneuploidy screening options have been less robust for twin pregnancies than for singletons6, whereas the miscarriage risk associated with invasive diagnostic procedures is higher in twins7. Preliminary data have suggested that NIPT is a feasible test option for twin gestations8, 9, 10. Currently, due to the paucity of reported studies in twins, professional societies and others have called for more studies on NIPT performance in twin gestations11, 12, 13, 14.…”

Section: Introductionmentioning

confidence: 99%

“…Although the total fetal fraction has been shown to be as much as 35% higher in twin pregnancies when compared with singletons10, the fetal fraction per twin is lower8, 9. Furthermore, it has been shown that individual cfDNA contribution from each twin could differ by as much as two‐fold15, 16.…”

Section: Introductionmentioning

confidence: 99%

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Aneuploidy screening by non‐invasive prenatal testing in twin pregnancy

Fosler

Winters

Jones

et al. 2017

Ultrasound in Obstet & Gyne

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ObjectivesTo describe our experience with non‐invasive prenatal testing (NIPT) in twin pregnancy.MethodsTwo sets of maternal blood samples from twin pregnancies were analyzed at our laboratory using NIPT: 115 stored samples from pregnancies with known outcome (Clinical Study A) and 487 prospectively collected samples for which outcomes were requested from providers (Clinical Study B). NIPT was used to screen for the presence of fetal aneuploidy on chromosomes 13, 18, 21, X and Y in all cases, and results were compared with outcomes when known.ResultsIn Clinical Study A, all 115 samples were classified correctly by NIPT: three cases of trisomy 21 (one fetus affected), one of monochorionic trisomy 18 (both fetuses affected) and 111 euploid. In Clinical Study B, a NIPT result was reported for 479 (98.4%) of the 487 samples. Aneuploidy was detected or suspected in nine (1.9%) cases: seven cases of trisomy 21 detected, one case of trisomy 21 suspected and one case with trisomy 21 detected and trisomy 18 suspected. Information on aneuploidy outcome was available for 171 (35.7%) cases in Clinical Study B. Of the nine cases with aneuploidy detected or suspected, six were confirmed to be a true positive in at least one twin based on karyotype or birth outcome and two were suspected to be concordant based on ultrasound findings; the one known discordant result was for the aneuploidy suspected case. No false negatives were reported.Conclusion NIPT performed well in the detection of trisomy 21 in twin pregnancy, with a combined false‐positive frequency for trisomies 13, 18 and 21 of 0% for Clinical Study A and 0.2% for Clinical Study B. © 2016 Illumina. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Aneuploidy screening by non‐invasive prenatal testing in twin pregnancy

Fosler

Winters

Jones

et al. 2017

Ultrasound in Obstet & Gyne

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“…Multiple gestation pregnancies have been reported to have higher fetal fractions. 12,14 Therefore, group comparisons of ccf DNA levels and fetal fractions were conducted after excluding data from the 16 sets of twins. The twin results were, however, included in the analyses of demographic information and z-scores.…”

Section: Resultsmentioning

confidence: 99%

Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies

Lambert-Messerlian

Kloza

Williams

et al. 2014

Genetics in Medicine

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Advances in molecular technologies have resulted in the introduction of next-generation sequencing of maternal plasma DNA for prenatal identification of Down syndrome and other common trisomies. 1,2 Circulating cell-free (ccf) DNA of placental/fetal origin 3 in the maternal circulation is thought to be released by apoptotic cells of the placenta, 4 and the success of next-generation sequencing is dependent on the percentage of fetal (placental) DNA present in maternal plasma (the fetal fraction). The higher the fetal fraction, the more easily a trisomy or other aneuploidy can be detected. On average, 13% of ccf DNA in maternal plasma is of fetal (placental) origin, and fetal fractions of less than 4% may not be sufficient for reliable testing. 1 First and second trimester maternal serum marker levels are known to be altered in pregnancies conceived using assisted reproductive technologies (ART) versus those conceived naturally (controls). [5][6][7][8][9][10] In particular, secretory products of the placenta, such as human chorionic gonadotropin and inhibin A, are 10-30% higher in pregnancies from ART relative to control pregnancies. The cause of the increased secretion is not known. Regardless, serum marker levels can be adjusted so that screening performance in ART pregnancies is comparable with that of controls. Given that a portion of ccf DNA also is released by placental cells, albeit by a different mechanism, we sought to explore the possibility that the levels of ccf DNA also differed between ART and control pregnancies. If ART pregnancies were to release at least as much fetal-specific ccf DNA into maternal blood as do naturally conceived pregnancies, this could reassure clinicians that next-generation testing in ART pregnancies would perform at least as well as in naturally conceived pregnancies. In addition, we examined the chromosome-specific z-score and the final interpretation of the testing in the ART and control pregnancies. MATERIALS AND METHODSSamples for this study were selected from among those reported earlier as part of a multicenter international clinical validation of a next-generation sequencing test for Down syndrome. 1Purpose: We sought to compare measurements of circulating cellfree DNA as well as Down syndrome test results in women with naturally conceived pregnancies with those conceived using assisted reproductive technologies.Methods: Data regarding assisted reproductive technologies were readily available from seven enrollment sites participating in an external clinical validation trial of nested case/control design. Measurements of circulating cell-free fetal and total DNA, fetal fraction (ratio of fetal to total DNA), chromosome-specific z-scores, and karyotype results were available for analysis.Results: Analyses were restricted to 632 euploid (5.2% assisted reproductive technologies) and 73 Down syndrome (13.7% assisted reproductive technologies), including 16 twin pregnancies. No differences were found for fetal or total circulating cell-free DNA, or for the fetal fraction in ...

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“…The MaterniT21 PLUS test sensitivity ranges from 99.1% for trisomy 21, > 99.9% for trisomy 18, and 91.7% for trisomy 13, while maintaining a very low falsepositive rate. Data from the validation studies are showed in Table 2 [7,28,42,58]. The analytical performance of selective microdeletions/duplications and trisomy 16/22, was > 99% regarding specificity, while sensitivity was 60-86% for 3-6 Mb deletions, 85-90% for 7-11 Mb deletions and > 99% for trisomy 16/22 [30,58].…”

Section: Maternit21 Plus (Sequenom Laboratories)mentioning

confidence: 99%

Non-invasive prenatal testing (NIPT): limitations on the way to become diagnosis

Kotsopoulou¹,

Tsoplou²,

Mavrommatis

et al. 2015

Diagnosis

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With the discovery of existing circulating cellfree fetal DNA (ccffDNA) in maternal plasma and the advent of next-generation sequencing (NGS) technology, there is substantial hope that prenatal diagnosis will become a predominately non-invasive process in the future. At the moment, non-invasive prenatal testing (NIPT) is available for high-risk pregnancies with significant better sensitivity and specificity than the other existing non-invasive methods (biochemical and ultrasonographical). Mainly it is performed by NGS methods in a few commercial labs worldwide. However, it is expected that many other labs will offer analogous services in the future in this fastgrowing field with a multiplicity of in-house methods (e.g., epigenetic, etc.). Due to various limitations of the available methods and technologies that are explained in detail in this manuscript, NIPT has not become diagnostic yet and women may still need to undergo risky invasive procedures to verify a positive finding or to secure (or even expand) a negative one. Efforts have already started to make the NIPT technologies more accurate (even at the level of a complete fetal genome) and cheaper and thus more affordable, in order to become diagnostic screening tests for all pregnancies in the near future.

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DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations

Cited by 158 publications

References 13 publications

Aneuploidy screening by non‐invasive prenatal testing in twin pregnancy

Aneuploidy screening by non‐invasive prenatal testing in twin pregnancy

Maternal plasma DNA testing for aneuploidy in pregnancies achieved by assisted reproductive technologies

Non-invasive prenatal testing (NIPT): limitations on the way to become diagnosis

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