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Mol. Hum. Reprod. Advance Access originally published online on March 25, 2004
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Molecular Human Reproduction, Vol. 10, No. 6, pp. 445-460, 2004
© European Society of Human Reproduction and Embryology 2004

Development and clinical application of a strategy for preimplantation genetic diagnosis of single gene disorders combined with HLA matching

F. Fiorentino1,3,4, A. Biricik1, H. Karadayi2, H. Berkil2, G. Karlikaya2, S. Sertyel2, D. Podini3, M. Baldi1, M.C. Magli1, L. Gianaroli1 and S. Kahraman2

1EmbryoGen (Centre for Preimplantation Genetic Diagnosis), Rome, 2Reproductive Endocrinology and Genetics Unit, Istanbul Memorial Hospital, Istanbul, Turkey and 3GENOMA (Molecular Genetics Laboratory), Rome, Italy

4 To whom correspondence should be addressed at: EmbryoGen (Preimplantation Genetic Diagnosis Centre), Via Po, 102 00198 Rome. Italy. e-mail: fiorentino{at}embryogen.it

Preimplantation HLA matching has recently emerged as a tool for couples desiring to conceive a potential donor progeny for transplantation in a sibling with a life-threatening disorder. In this paper we describe a strategy optimized for preimplantation genetic diagnosis (PGD) of haemoglobinopathies combined with HLA matching. This procedure involves a minisequencing-based genotyping of HLA regions A, B, C and DRB combined with mutation analysis of the gene regions involved by mutation. Analysis of at least eight polymorphic short tandem repeat (STR) markers scattered through the HLA complex has also been included to detect potential contamination and crossing-over occurrences between HLA genes. The above assay can also be used for preimplantation HLA matching as a primary indication. The strategy was clinically applied for HLA matching in 17 cycles (14 for ß-thalassaemia, one for Wiscott–Aldrich syndrome and two for leukaemia). A reliable HLA genotype was achieved in 255/266 (95.9%) of the blastomeres. In total, 22 (14.8%) embryos were obtained that were HLA-matched with the affected siblings, 14 (9.4%) of which were unaffected and transferred back to the patients. Four clinical pregnancies were obtained, three of which (one twin, two singletons) are ongoing and were confirmed as healthy and HLA-identical with the affected children. Minisequencing-based HLA typing combined with HLA STR haplotyping has been shown to be a reliable strategy for preimplantation HLA matching. The major advantage of this approach is that the validation of a single assay can be done once and then used for the majority of the patients, reducing notably time needed for preclinical set-up of each case.

Key words: haematopoietic stem cell transplantation/microsatellites/minisequencing/preimplantation HLA matching/preimplantation genetic diagnosis


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