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Non-invasive prenatal measurement of the fetal genome

An Erratum to this article was published on 08 August 2012

Abstract

The vast majority of prenatal genetic testing requires invasive sampling. However, this poses a risk to the fetus, so one must make a decision that weighs the desire for genetic information against the risk of an adverse outcome due to hazards of the testing process. These issues are not required to be coupled, and it would be desirable to discover genetic information about the fetus without incurring a health risk. Here we demonstrate that it is possible to non-invasively sequence the entire prenatal genome. Our results show that molecular counting of parental haplotypes in maternal plasma by shotgun sequencing of maternal plasma DNA allows the inherited fetal genome to be deciphered non-invasively. We also applied the counting principle directly to each allele in the fetal exome by performing exome capture on maternal plasma DNA before shotgun sequencing. This approach enables non-invasive exome screening of clinically relevant and deleterious alleles that were paternally inherited or had arisen as de novo germline mutations, and complements the haplotype counting approach to provide a comprehensive view of the fetal genome. Non-invasive determination of the fetal genome may ultimately facilitate the diagnosis of all inherited and de novo genetic disease.

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Figure 1: Molecular counting strategies for measuring the fetal genome non-invasively from maternal blood only.
Figure 2: Non-invasively determining genome-wide fetal inheritance of maternal haplotypes via haplotype counting of maternal plasma DNA with at least 99.8% accuracy over 99.2% of the genome in three maternal plasma samples.
Figure 3: Reconstruction of paternally inherited chromosomes non-invasively based on imputation using observed non-maternal alleles.
Figure 4: Exome sequencing of P1 maternal plasma DNA in all three trimesters to determine maternal and fetal genotypes.

References

  1. 1

    Mandel, P. & Metais, P. Les acides nucléiques du plasma sanguin chez l’homme. C. R. Acad. Sci. Paris 142, 241–243 (1948)

    CAS  Google Scholar 

  2. 2

    Lo, Y. M. et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am. J. Hum. Genet. 62, 768–775 (1998)

    CAS  Article  Google Scholar 

  3. 3

    Bodurtha, J. & Strauss, J. F., III Genomics and perinatal care. N. Engl. J. Med. 366, 64–73 (2012)

    CAS  Article  Google Scholar 

  4. 4

    Fan, H. C., Blumenfeld, Y. J., Chitkara, U., Hudgins, L. & Quake, S. R. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc. Natl Acad. Sci. USA 105, 16266–16271 (2008)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Sehnert, A. J. et al. Optimal detection of fetal chromosomal abnormalities by massively parallel DNA sequencing of cell-free fetal DNA from maternal blood. Clin. Chem. 57, 1042–1049 (2011)

    CAS  Article  Google Scholar 

  6. 6

    Bianchi, D. W. et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obst. Gynecol. 119, 890–901 (2012)

    CAS  Article  Google Scholar 

  7. 7

    Palomaki, G. E. et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet. Med. 14, 296–305 (2012)

    CAS  Article  Google Scholar 

  8. 8

    Palomaki, G. E. et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet. Med. 13, 913–920 (2011)

    CAS  Article  Google Scholar 

  9. 9

    Ehrich, M. et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am. J. Obstet. Gynecol. 204, 205.e1–211.e11 (2011)

    Article  Google Scholar 

  10. 10

    Chiu, R. W. et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. Br. Med. J. 342, c7401 (2011)

    Article  Google Scholar 

  11. 11

    Lo, Y. M. et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci. Transl. Med. 2, 61ra91 (2010)

    CAS  Article  Google Scholar 

  12. 12

    Fan, H. C. & Quake, S. R. In principle method for noninvasive determination of the fetal genome. Preprint at http://precedings.nature.com/documents/5373/version/1 (2010)

  13. 13

    Macintyre, S. & Sooman, A. Non-paternity and prenatal genetic screening. Lancet 338, 869–871 (1991)

    CAS  Article  Google Scholar 

  14. 14

    Bellis, M. A., Hughes, K., Hughes, S. & Ashton, J. R. Measuring paternal discrepancy and its public health consequences. J. Epidemiol. Community Health 59, 749–754 (2005)

    Article  Google Scholar 

  15. 15

    Fan, H. C., Wang, J., Potanina, A. & Quake, S. R. Whole-genome molecular haplotyping of single cells. Nature Biotechnol. 29, 51–57 (2011)

    CAS  Article  Google Scholar 

  16. 16

    The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

  17. 17

    Marchini, J. et al. A comparison of phasing algorithms for trios and unrelated individuals. Am. J. Hum. Genet. 78, 437–450 (2006)

    CAS  Article  Google Scholar 

  18. 18

    White, R. A., III, Blainey, P. C., Fan, H. C. & Quake, S. R. Digital PCR provides sensitive and absolute calibration for high throughput sequencing. BMC Genomics 10, 116 (2009)

    Article  Google Scholar 

  19. 19

    Clark, M. J. et al. Performance comparison of exome DNA sequencing technologies. Nature Biotechnol. 29, 908–914 (2011)

    CAS  Article  Google Scholar 

  20. 20

    Kinde, I., Wu, J., Papadopoulos, N., Kinzler, K. W. & Vogelstein, B. Detection and quantification of rare mutations with massively parallel sequencing. Proc. Natl Acad. Sci. USA 108, 9530–9535 (2011)

    ADS  Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank E. Kogut and staff of the Division of Perinatal Genetics and the General Clinical Research Center of Stanford University for coordination of patient recruitment; R. Wong for initial sample processing of clinical samples; N. Neff, G. Mantalas, B. Passarelli and W. Koh for their help in sequencing library preparation and data analysis.

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Authors

Contributions

H.C.F., W.G. and S.R.Q. conceived the study. H.C.F., W.G. and J.W. performed experiments. H.C.F., W.G. and J.W. analysed the data. Y.J.B. and Y.Y.E.-S. coordinated patient recruitment. H.C.F., W.G., J.W. and S.R.Q. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Stephen R. Quake.

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Competing interests

S.R.Q. is a founder and shareholder of Fluidigm Corporation and Helicos BioSciences. S.R.Q. and H.C.F. are shareholders of Verinata Health.

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This file contains Supplementary Text, Supplementary Tables 1-3 and Supplementary Figures 1-14. (PDF 5994 kb)

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Fan, H., Gu, W., Wang, J. et al. Non-invasive prenatal measurement of the fetal genome. Nature 487, 320–324 (2012). https://doi.org/10.1038/nature11251

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