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Mol. Hum. Reprod. Advance Access published online on September 18, 2008
Molecular Human Reproduction, 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, 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, Maastricht University Medical Centre 2Departments of Obstetrics & Gynaecology, Maastricht University Medical Centre 3Department of Genetics and Cell Biology, division Complex Genetics, and School for Oncology and Developmental Biology 4 GROW and School for Nutrition, Toxicology and Metabolism 5 NUTRIM Maastricht University, The Netherlands 6Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, United Kingdom.

Address for correspondence: J.C.F.M. Dreesen, Maastricht University Medical Centre, Department of Clinical Genetics, PO box 5800, P.Debyelaan 25, 6202 AZ Maastricht, The Netherlands. Tel. number: +31-433881916 Fax number: +31-433877877 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 four post fertilization. To establish the validity of PGD-PCR procedure and the diagnostic value, misdiagnosis rate, false negative rate and negative predictive value were calculated respectively. 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% was found. The negative predictive value was 96.1%. Poor morphology day four embryos (class 1) were overrepresented in the embryo group in which the blastomere genotype was not confirmed by the whole embryo genotype. 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%, false negative rate of 0.5% and a negative predictive value of 99.3%. The two blastomere biopsy revealed a significant higher positive predictive value, lowering the misdiagnosis rate, whereas the negative predictive value remained the same. In conclusion PGD-PCR procedure is a valid diagnostic method for selecting unaffected embryos for ET. Misdiagnosis rate and false negative rate 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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