Trisomy 2 mosaicism with high trisomic fraction identified by cell-free DNA screening is associated with an increased risk for adverse feto-placental outcomes

Mark D Pertile1,2, Nicola Flowers1, Grace Shi1, Olivia Giouzeppos1, Shelley Baeffel1, Ian Burns1, Tom Harrington1, Rebecca Manser1, Absera Tsegay1, Ralph Oertel1, Fiona Norris1.

1 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, VIC, 3052
2 Department of Paediatrics, University of Melbourne, Parkville, VIC, 3010.

Whole genome sequencing (WGS) of maternal plasma cell-free DNA (cfDNA) can potentially evaluate all 24 chromosomes to identify abnormalities of the placenta or fetus. We have systematically analysed WGS data from all chromosomes to identify rare autosomal trisomies (RATs) to improve our understanding of discordant findings and feto-placental biology. Here, we describe our experience with prenatally ascertained trisomy 2 mosaicism.

Trisomy 2 usually presents as a benign mosaic finding at CVS, commonly confined to the chorionic mesenchyme and rarely involving the cytotrophoblast. Involvement of the cytotrophoblast increases the likelihood that the conception is trisomic, with subsequent increased risk for true fetal mosaicism (TFM) and uniparental disomy (UPD) following trisomy rescue.

We have identified six cases of trisomy 2 mosaicism ascertained by cfDNA screening. In five samples, the mean ratio of the trisomic fraction (TF) to fetal fraction (FF) approached 1.0 (TF:FF = 0.83 ± SD 0.09), consistent with very high levels of trisomy 2 cells in placental cytotrophoblast. These pregnancies were associated with TFM, UPD, intrauterine growth restriction (IUGR) and/or intrauterine fetal demise (IUFD), in keeping with a meiotic origin of the trisomy. In the sixth , the mean ratio of the trisomic fraction to fetal fraction was low (TF:FF = 0.25). This pregnancy had normal prenatal investigations and continued to an uncomplicated term delivery. Examination of chorionic villi from the term placenta indicated the trisomy 2 mosaicism was most likely of mitotic (post zygotic) origin.

This data, together with our experience involving other RATs, suggests cfDNA screening can potentially identify those pregnancies at highest risk for relevant fetal-placental complications.



Dr. Mark Pertile is a senior medical scientist who specialises in reproductive cytogenetics and genomics. He is currently the Deputy Director of Laboratories at VCGS, Heads the Division of Reproductive Genetics and is also Head of the NIPT Laboratory. Mark has a long standing interest in early human embryology and development. He works with a team that applies molecular cytogenetics and genomics technologies to help identify the causes and origins of genomic conditions early in pregnancy.

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