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Mol. Hum. Reprod. Advance Access originally published online on September 18, 2008
Molecular Human Reproduction 2008 14(10):573-579; doi:10.1093/molehr/gan052
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Validation of preimplantation genetic diagnosis by PCR analysis: genotype comparison of the blastomere and corresponding embryo, implications for clinical practice

J. Dreesen1,4,7, M. Drüsedau1, H. Smeets1,4, C. de Die-Smulders1,4, E. Coonen1,2, J. Dumoulin2, M. Gielen3,5,6, J. Evers2,4, J. Herbergs1,4 and J. Geraedts1,4

1Departments of Clinical Genetics 2 Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, The Netherlands 3Department of Genetics and Cell Biology, division Complex Genetics 4GROW, School for Oncology and Developmental Biology 5 NUTRIM, School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands 6Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK

7 Correspondence address. Maastricht University Medical Centre, Department of Clinical Genetics, PO Box 5800, P.Debyelaan 25, 6202 AZ Maastricht, The Netherlands. E-mail: Jos.Dreesen{at}Gen.unimaas.nl

The aim of this study was to validate the overall preimplantation genetic diagnosis (PGD)–PCR procedure and to determine the diagnostic value. Genotyped embryos not selected for embryo transfer (ET) and unsuitable for cryopreservation after PGD were used for confirmatory analysis. The PGD genotyped blastomeres and corresponding embryos were compared, and morphology was scored on Day 4 post fertilization. To establish the validity of the PGD–PCR procedure and the diagnostic value, misdiagnosis rate, false-negative rate and negative predictive value were calculated. Moreover, comparison on the validity was made for the biopsy of one or two blastomeres. For the total embryo group (n = 422), a misdiagnosis rate of 7.1% and a false-negative rate of 3.1% were found. The negative predictive value was 96.1%. Poor morphology Day 4 embryos (Class 1) were over-represented in the embryo group in which the blastomere genotype was not confirmed by the whole embryo genotype. The misdiagnosis rate of Class 1 embryos was 12.5% and the false-negative rate 17.1%. Exclusion of these embryos resulted in a misdiagnosis rate of 6.1%, a false-negative rate of 0.5% and a negative predictive value of 99.3%. The two blastomere biopsies revealed a significant higher positive predictive value, lowering the misdiagnosis rate, whereas the negative predictive value remained the same. In conclusion, the PGD–PCR procedure is a valid diagnostic method to select unaffected embryos for ET. The misdiagnosis and false-negative rates decrease by rejecting Class 1 embryos for ET. The biopsy of a second blastomere improves the positive predictive value, lowering the misdiagnosis rate.

Key words: preimplantation genetic diagnosis/preimplantation diagnosis/sensitivity/negative predictive value/embryo morphology

Submitted on July 3, 2008; resubmitted on September 11, 2008; accepted on September 15, 2008.


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