Abstract

BackgroundThe American College of Obstetrics and Gynecology (ACOG) and Maternal Fetal Medicine (MFM) Societies recommended that abnormal cfDNA fetal results should be confirmed by amniocentesis and karyotyping. Our results demonstrate that normal cfDNA results inconsistent with high-resolution abnormal ultrasounds should be confirmed by karyotyping following a substantial frequency of incorrect cfDNA results.MethodsHistorical review of our ~4,000 signed prenatal karyotypes found ~24% of reported abnormalities would not have been detected by cfDNA. Akron Children’s Hospital Cytogenetics Laboratory has completed 28 abnormal cfDNA cases among the 112 amniocenteses karyotyped.ResultsFollowing abnormal cfDNA results our karyotypes confirmed only 60% of the cfDNA results were consistent. Our cases found a normal cfDNA test result followed by a 20 weeks anatomical ultrasound detected a false negative trisomy 18 cfDNA result. One cfDNA result that reported trisomy 21 in the fetus was confirmed by karyotyping which also added an originally undetected balanced reciprocal translocation. Another reported karyotyped case followed by a repeated microarray of pure fetal DNA, together revealed one phenotypically normal newborn with a complex mosaic karyotype substantially decreasing the newborn’s eventual reproductive fitness. This second case establishes the importance of karyotyping the placenta and cord or peripheral blood when inconsistent or mosaic results are identified following an abnormal cfDNA result with a normal newborn phenotype without a prenatal karyotype.ConclusionsThese Maternal Fetal Medicine referrals demonstrate that positive NIPT results identify an increased abnormal karyotypic frequency as well as a substantial proportion of discordant fetal results. Our results found: (1) a normal NIPT test result followed by a 20 week anatomical ultrasound detected a false negative trisomy 18 NIPT result, (2) a substantial proportion of abnormal NIPT tests identify chromosomal mosaicism that may or may not be confined to the placenta, (3) follow up karyotyping should be completed on the newborn placenta and peripheral blood when the amniocyte karyotype does not confirm the NIPT reported abnormality in order to identify ongoing risk of developing mosaic symptoms, and (4) karyotyping all high risk fetuses tested by amniocentesis defines the 24% of chromosome abnormalities not currently screened by NIPT.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0569-y) contains supplementary material, which is available to authorized users.

Highlights

  • The American College of Obstetrics and Gynecology (ACOG) and Maternal Fetal Medicine (MFM) Societies recommended that abnormal circulating fetal DNA (cfDNA) fetal results should be confirmed by amniocentesis and karyotyping

  • Prior to offering one of the circulating fetal DNA screening tests to pregnant mothers, patients referred to our regional Maternal Fetal Medicine specialists are counseled that these Noninvasive Prenatal Testing (NIPT) tests for circulating placental DNA in maternal circulation are screening tests and as such are not entirely diagnostic

  • Following a positive screening test result, amniocentesis was offered to all the cases with an abnormal fetal result in circulating placental DNA test result according to our initial protocol and confirmed by the ACOG recommended protocol [12]

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Summary

Introduction

The American College of Obstetrics and Gynecology (ACOG) and Maternal Fetal Medicine (MFM) Societies recommended that abnormal cfDNA fetal results should be confirmed by amniocentesis and karyotyping. Other investigators reported the majority of circulating fetal DNA (cfDNA) in maternal plasma is derived primarily from the trophoblast [6, 7]a This was selected as a preferred source of fetal DNA to be tested because it has an average half-life of 16.3 min post-delivery so that levels are undetectable within hours post-partum [8, 9]. This cfDNA can be detected reliably in the maternal circulation by 7 weeks gestation and its relative proportion of total circulating DNA increases with gestational age [7]. A few selected chromosome-specific sites were tagged along with control sites, all tags sequenced millions of times, and the total frequencies compared to normal DNAs to identify whole chromosome aneuploidy in the admixed fetal DNA: trisomy when increased and monosomy when decreased

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