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Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection

Nature Medicine 13, 218–223 (2007) | Download Citation

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Abstract

Current methods for prenatal diagnosis of chromosomal aneuploidies involve the invasive sampling of fetal materials using procedures such as amniocentesis or chorionic villus sampling and constitute a finite risk to the fetus. Here, we outline a strategy for fetal chromosome dosage assessment that can be performed noninvasively through analysis of placental expressed mRNA in maternal plasma. We achieved noninvasive prenatal diagnosis of fetal trisomy 21 by determining the ratio between alleles of a single-nucleotide polymorphism (SNP) in PLAC4 mRNA, which is transcribed from chromosome 21 and expressed by the placenta, in maternal plasma. PLAC4 mRNA in maternal plasma was fetal derived and cleared after delivery. The allelic ratios in maternal plasma correlated with those in the placenta. Fetal trisomy 21 was detected noninvasively in 90% of cases and excluded in 96.5% of controls.

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Acknowledgements

This project was supported by the Innovation and Technology Fund of the Hong Kong SAR Government (ITS/195/01) and the Li Ka Shing Foundation.

Author information

    • Y M Dennis Lo
    • , Nancy B Y Tsui
    • , Rossa W K Chiu
    •  & Chunming Ding

    These authors contributed equally to this work.

Affiliations

  1. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

    • Y M Dennis Lo
    • , Rossa W K Chiu
    •  & Chunming Ding

  2. Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

    • Y M Dennis Lo
    • , Nancy B Y Tsui
    • , Rossa W K Chiu
    •  & Macy M S Heung

  3. Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

    • Tze K Lau
    •  & Tse N Leung

  4. Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London SE5 9RS, UK.

    • Ageliki Gerovassili
    •  & Kypros H Nicolaides

  5. Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

    • Yongjie Jin
    •  & Chunming Ding

  6. Bioinformatics Program and Center for Advanced Biotechnology, Boston University, 36 Cummington Street, Boston, Massachusetts 02118, USA.

    • Charles R Cantor

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Competing interests

Y.M.D.L., N.B.Y.T., R.W.K.C., C.R.C. and C.D. have filed a patent application on the RNA-SNP allelic ratio technology described in this paper.

Y.M.D.L. has equity in Plasmagene Biosciences Limited.

C.R.C. and C.D. have equity in Sequenom Inc.

C.R.C. is the Chief Scientific Officer of Sequenom Inc.

Corresponding author

Correspondence to Y M Dennis Lo.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    MS tracings of the PLAC4 SNP genotype in DNA samples of maternal blood cells and placentas and RNA samples of placentas and maternal plasma.

  2. 2.

    Supplementary Table 1

    Transcripts from chromosome 21 with high relative and absolute placental tissue expression as identified by the micorarray data mining strategy.

  3. 3.

    Supplementary Table 2

    Sequences and allelic frequencies of four polymorphic SNPs located in the transcribed regions of PLAC4.

  4. 4.

    Supplementary Table 3

    PLAC4 SNP genotype analysis using maternal blood cell and placental DNA as well as placental and maternal plasma RNA obtained from pregnant women carrying euploid fetuses.

  5. 5.

    Supplementary Table 4

    Primer sequences of the RNA-SNP allelic ratio assay involving the PLAC4 SNP, rs8130833.

  6. 6.

    Supplementary Table 5

    PCR primers for direct sequencing of PLAC4.

  7. 7.

    Supplementary Methods

  8. 8.

    Supplementary Note

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DOI

https://doi.org/10.1038/nm1530

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