Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Marfan syndrome as a paradigm for transcript-targeted preimplantation diagnosis of heterozygous mutations

Nature Medicine volume 1, pages 798–803 (1995)Cite this article

Abstract

Among the many clinical applications of the polymerase chain reaction (PCR) is its potential use in preimplantation diagnosis of genetic disorders. Performing PCR on single blastomeres from early cleavage stage (six-to eight-cell) human embryos should, in principle, enable reliable determination of disease status for certain inherited conditions. However, reports of misdiagnoses using this technique have diminished enthusiasm for its widespread clinical use. One principal source of error is the propensity for genome-targeted PCR to exclusively amplify one allele in reactions assaying a single heterozygous diploid cell. Complete reaction failure is also common. Employing the Marfan syndrome (MFS) as a paradigm, we have developed a reliable, reverse transcription-PCR-based method of genotyping single cells that overcomes these obstacles. The technique should facilitate accurate preimplantation diagnosis of MFS and other selected genetic diseases caused by heterozygous or compound-heterozygous mutations.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Handyside, A.H. et al. Biopsy of human preimplantation embryos and sexing by DNA amplification. Lancet ii, 532–535 (1989).

    Google Scholar 

  2. Handyside, A.H., Lesko, J.G., Tarin, J., Winston, R. & Hughes, M.R. Birth of a normal girl following preimplantation diagnosis for cystic fibrosis. New Engl. J. Med. 327, 905–909 (1992).

    Article  CAS  Google Scholar 

  3. Grifo, J.A. et al. Pregnancy after embryo biopsy and coamplification of DNA from X and Y chromosomes. JAMA 268, 727–729 (1992).

    Article  CAS  Google Scholar 

  4. Grifo, J.A. et al. Healthy deliveries from biopsied human embryos. Hum. Reprod. 9, 912–916 (1994).

    Article  CAS  Google Scholar 

  5. Handyside, A.H., Kontogianni, E.H., Hardy, K. & Winston, R.M.L. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 344, 768–770 (1990).

    Article  CAS  Google Scholar 

  6. Handyside, A.H. & Delhanty, J.D.A. Cleavage stage biopsy of human embryos and diagnosis of X-chomosome-linked recessive disease. in Preconception and Preimplantation Diagnosis of Human Genetic Disease (ed. Edwards, R.G.) 239–270 (Cambridge Univ. Press, Cambridge, 1993).

    Google Scholar 

  7. Verlinsky, Y. et al. Preconception and preimplantation diagnosis for cystic fibrosis. Prenatal Diag. 12, 103–110 (1992).

    Article  CAS  Google Scholar 

  8. Trounson, A.L. Preimplantation genetic diagnosis — Counting chickens before they hatch? Hum. Reprod. 7, 583–584 (1992).

    Article  CAS  Google Scholar 

  9. Pickering, S.J., McConnell, J.M., Johnson, M.H. & Braude, P.R. Reliability of detection by polymerase chain reaction of the sickle cell-containing region of the b-globin gene in single human blastomeres. Hum. Reprod. 7, 630–636 (1992).

    Article  CAS  Google Scholar 

  10. Arnheim, N. Preimplantation genetic diagnosis — A rolling stone gathers no moss! Hum. Reprod. 7, 1481 (1992).

    Article  CAS  Google Scholar 

  11. Navidi, W. & Arnheim, N. Using PCR in preimplantation genetic disease diagnosis. Hum. Reprod. 6, 836–849 (1991).

    Article  CAS  Google Scholar 

  12. Zhang, L. et al. Whole genome amplification from a single cell: Implications for genetic analysis. Proc. natn. Acad. Sci. U.S.A. 89, 5847–5851 (1992).

    Article  CAS  Google Scholar 

  13. Cui, K.H. & Matthews, C.D. Preimplantation diagnosis. Comment in Lancet 343, 972–973 (1994).

    Article  CAS  Google Scholar 

  14. Handyside, A. Prospects for the clinical application of preimplantation diagnosis: The tortoise or the hare? Hum. Reprod. 7, 1481–1483 (1992).

    Article  CAS  Google Scholar 

  15. Kontogianni, E.H., Hardy, K. & Handyside, A.H. Co-amplification of X- and Y-specific sequences for sexing preimplantation human embryos. in Preimplantation Genetics (eds Verlinsky, Y. & Kuliev, A) 139–145 (Plenum, New York, 1991).

    Chapter  Google Scholar 

  16. Snabes, M.C. et al. Preimplantation single-cell analysis of multiple genetic loci by whole-genome amplification. Proc. natn. Acad. Sci. U.S.A. 91, 6181–6185 (1994).

    Article  CAS  Google Scholar 

  17. Kristjansson, K. et al. Preimplantation single cell analyses of dystrophin gene deletions using whole genome amplification. Nature Genet. 6, 19–23 (1994).

    Article  CAS  Google Scholar 

  18. Cui, X. et al. Single sperm typing: Determination of genetic distance between the γ-globin and parathyroid hormone loci. Proc. natn. Acad. Sci. U.S.A. 86, 9389–9393 (1993).

    Article  Google Scholar 

  19. Li, A. et al. Amplification and analysis of DNA sequences in single human sperm and diploid cells. Nature 335, 414–419 (1988).

    Article  CAS  Google Scholar 

  20. Boehnke, M., Arnheim, N., Li, H. & Collins, F.S. Fine-structure genetic mapping of human chromosomes using the polymerase chain reaction on single sperm: Experimental design considerations. Am. J. hum. Genet. 45, 21–32 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. McKusick, V.A. Heritable Disorders of Connective Tissue. 4th edn (Mosby, St. Louis, 1977).

    Google Scholar 

  22. Pyeritz, R.E. & McKusick, V.A. The Marfan syndrome: Diagnosis and management. New Engl. J. Med. 300, 772–777 (1977).

    Article  Google Scholar 

  23. Dietz, H.C. et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352, 337–339 (1991).

    Article  CAS  Google Scholar 

  24. Dietz, H.C., Saraiva, J.M., Pyeritz, R.E., Cutting, G.R. & Francomano, C.A. Clustering of fibrillin (FBN1) missense mutations in Marfan syndrome patients at cysteine residues in EGF-like domains. Hum. Mutat. 1, 366–374 (1992).

    Article  CAS  Google Scholar 

  25. Corson, G.M., Chalberg, S.C., Dietz, H.C., Charbonneau, N.L. & Sakai, L.Y. Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end. Genomics 17, 476–484 (1993).

    Article  CAS  Google Scholar 

  26. Hewett, D., Lynch, J., Child, A., Firth, H. & Sykes, B. Differential allelic expression of a fibrillin gene (FBN1) in patients with Marfan syndrome. Am. J. hum. Genet. 52, 447–452 (1994).

    Google Scholar 

  27. McKusick, V.A. Mendelian Inheritance in Man. 11th edn (Johns Hopkins Univ. Press, Baltimore, Maryland, 1993).

    Google Scholar 

  28. Liu, J., Lissens, W., Devroey, P., Van Steirteghem, A. & Liebaers, I. Amplification of X- and Y-chromosome-specific regions from single human blastomeres by polymerase chain reaction for sexing of preimplantation embryos. Hum. Reprod. 9, 716–720 (1994).

    Article  CAS  Google Scholar 

  29. Muggleton-Harris, A.L. Inherited genetic defects: Analysis and diagnosis at the cellular level in preimplantation embryos. Intl. Rev. Cytol. 151, 1–27 (1994).

    Article  CAS  Google Scholar 

  30. Nijbroek, G. et al. Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Am. J. hum. Genet. 57, 8–21 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bridges, A.B. et al. Marfan syndrome in a large family: Response of family members to a screening programme. J. med. Genet. 29, 81–85 (1992).

    Article  CAS  Google Scholar 

  32. Pereira, L. et al. Diagnosis of Marfan syndrome: A molecular approach to the stratification of cardiovascular risk within families with Marfan's syndrome. New Engl. J. Med. 331, 148–153 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Pediatrics, Medicine,

    Zayd A. Eldadah & Harry C. Dietz

  2. Molecular Biology & Genetics, Center for Medical Genetics, The Johns Hopkins University School of Medicine, 1170 Ross Research Building, 720 Rutland Avenue, Baltimore, Maryland, 21205, USA

    Zayd A. Eldadah & Harry C. Dietz

  3. Center for Reproductive Medicine and Infertility, Cornell University Medical College, Room HT 300, 505 East 70th Street, New York, New York, 10021, USA

    Jamie A. Grifo

Authors
  1. Zayd A. Eldadah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jamie A. Grifo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harry C. Dietz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eldadah, Z., Grifo, J. & Dietz, H. Marfan syndrome as a paradigm for transcript-targeted preimplantation diagnosis of heterozygous mutations. Nat Med 1, 798–803 (1995). https://doi.org/10.1038/nm0895-798

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0895-798

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing