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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mandel, P. & Metais, P. Les acides nucléiques du plasma sanguin chez l’homme. C. R. Acad. Sci. Paris 142, 241–243 (1948)
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)
Bodurtha, J. & Strauss, J. F., III Genomics and perinatal care. N. Engl. J. Med. 366, 64–73 (2012)
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)
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)
Bianchi, D. W. et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obst. Gynecol. 119, 890–901 (2012)
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)
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)
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)
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)
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)
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)
Macintyre, S. & Sooman, A. Non-paternity and prenatal genetic screening. Lancet 338, 869–871 (1991)
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)
Fan, H. C., Wang, J., Potanina, A. & Quake, S. R. Whole-genome molecular haplotyping of single cells. Nature Biotechnol. 29, 51–57 (2011)
The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)
Marchini, J. et al. A comparison of phasing algorithms for trios and unrelated individuals. Am. J. Hum. Genet. 78, 437–450 (2006)
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)
Clark, M. J. et al. Performance comparison of exome DNA sequencing technologies. Nature Biotechnol. 29, 908–914 (2011)
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)
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.
Author information
Authors and Affiliations
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
Ethics declarations
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.
Supplementary information
Supplementary Information
This file contains Supplementary Text, Supplementary Tables 1-3 and Supplementary Figures 1-14. (PDF 5994 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature11251
This article is cited by
-
An inexpensive semi-automated sample processing pipeline for cell-free RNA extraction
Nature Protocols (2023)
-
Noninvasive fetal genotyping of single nucleotide variants and linkage analysis for prenatal diagnosis of monogenic disorders
Human Genomics (2022)
-
Chromosomal phase improves aneuploidy detection in non-invasive prenatal testing at low fetal DNA fractions
Scientific Reports (2022)
-
Nanostructures in non-invasive prenatal genetic screening
Biomedical Engineering Letters (2022)
-
The fetus in the age of the genome
Human Genetics (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.