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placenta whispers II... tales of CPM and clinical impact

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Abstract Number: (223)

placenta whispers II... tales of CPM and clinical impact

Topic: Clinical Genetics

Presenting Author: Jenna Wardrop

Co-Authors: T. Boomer, Sequenom Laboratories; E. Almasri; P. Cacheris, Sequenom Laboratories; R. McCullough, Sequenom Laboratories

Session Type: Poster Presentation only


Introduction: Noninvasive prenatal testing (NIPT) for aneuploidy relies on the presence of circulating cell free DNA believed to be largely placental in origin. The genetic material in fetal and placental tissue matches in most pregnancies. However, discordance between these tissues can result from post zygotic non-disjunction or trisomy rescue, causing uneven distribution of cells between fetus and placenta. This is not a new limitation of NIPT technology1, 2. Fiverecently confirmed cases of confined placental mosaicism (CPM) identified by positive NIPT results are highlighted here.

Methods: Maternal blood samples submitted to Sequenom Laboratories® for MaterniT®21 PLUS and MaterniT® GENOME testing were subjected to DNA extraction, library preparation, and whole genome massively parallel sequencing as described by Jensen et al.3,4


These cases describe five pregnancies with positive NIPT results, negative amniocentesis, and confirmed CPM. These cases underscore how NIPT provides unprecedented insight into the chromosomal constitution of placental tissue.

CPM that would be otherwise unseen or minimized by traditional test methods confounds results both technically and clinically. NIPT mirrors short term CVS cultures (including FISH), both of which primarily examine the trophoblastic layer of the placenta. Trophoblasts are especially prone to mitotic error due the rapid cell division necessary for uterine wall attachment. Early differentiation of this placental layer makes it the most distantly related cell type compared to the relatively few cells that go onto form the fetus proper. Long term CVS cultures examine a mixture of trophoblast and villus core cells, the latter being more closely related to the fetus proper. Amniotic fluid samples contain cells from the epiblast of the inner cell mass of the embryo and most closely reflect the true constitution of the fetus.

Long term cell culture can bias analysis, since culture conditions favor normal, healthier cell lines and select against abnormal clones. Thus, analysis of mosaic cultured cells is likely to be an underrepresentation of the abnormal cells that existed in vivo.

CPM may be associated with varying degrees of placental dysfunction, and may present clinically as abnormal biochemical screening, fetal growth restriction, or preterm labor. Fetal growth restriction is directly associated with certain types of CPM. Specific CPM types are indistinguishable by NIPT and difficult to assess prenatally as a whole. CPM types I and III are indistinguishable by NIPT, while type II may allude NIPT altogether. Therefore, pregnancies that present with discordant ‘false positive’ NIPT results may warrant more conservative pregnancy management, as they may be at risk for placental dysfunction. Clinicians need to be aware of the various biological limitations of each testing modality, as well as cell culture impact on mosaic studies. Especially in the face of discrepant prenatal results, such awareness is essential for accurate clinical assessment and counseling and overall case interpretation.



  1. Boomer T, Cherny S, Miles J, et al. Placenta Whispers: Discordant noninvasive prenatal testing (NIPT) results and the role that confed placental mosaicism (CPM) plays. Poster presented at: 64th Annual Meeting of the American Society of Human Genetics; 2014 October 18-22; San Diego, CA.


  2. Boomer T, Dharajiya N, Paxton WB, et al. Disomic placentas, trisomic babies: reverse mosaicism and implications for noninvasive prenatal testing (NIPT). Poster session presented at: National Society of Genetic Counselors 33rd Annual Education Conference; 2014 Sep 17-20; New Orleans, LA.

3. Jensen TJ, Zwiefelhofer T, Tim RC, et al. High-throughput massively parallel sequencing for fetal aneuploidy detection from maternal plasma. PLoS One. 2013;8(3):e57381. doi: 10.1371/journal.pone.0057381. Epub 2013 Mar 6.

4. Lefkowitz RB, Tynan J, Liu T, et al. Clinical validation of a non-invasive

    prenatal test for genome-wide detection of fetal copy number variants.

    American Journal of Obstetrics & Gynecology. doi: http://dx.doi.org/10.1016/j.ajog.2016.02.030

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