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Mol. Hum. Reprod. Advance Access published online on March 25, 2004
Molecular Human Reproduction, doi:10.1093/molehr/gah055
© 2004 by Oxford University Press
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Received December 23, 2003
Revised February 17, 2004
Accepted February 22, 2004

Article

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

F. Fiorentino 1*, A. Biricik 2, H. Karadayi 3, H. Berkil 3, G. Karlikaya 3, S. Sertyel 3, D. Podini 4, M. Baldi 2, M.C. Magli 2, L. Gianaroli 2, S. Kahraman 3

1 EmbryoGen (Centre for Preimplantation Genetic Diagnosis), Rome, Italy; GENOMA (Molecular Genetics Laboratory), Rome, Italy; EmbryoGen (Preimplantation Genetic Diagnosis Centre), Via Po, 102 00198 Rome, Italy
2 EmbryoGen (Centre for Preimplantation Genetic Diagnosis), Rome, Italy
3 Reproductive Endocrinology and Genetics Unit, Istanbul Memorial Hospital, Istanbul, Turkey
4 GENOMA (Molecular Genetics Laboratory), Rome, Italy

* To whom correspondence should be addressed. E-mail: fiorentino{at}embryogen.it.


  Abstract

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 {beta}-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: Key words: haematopoietic stem cell transplantation/microsatellites/minisequencing/preimplantation HLA matching/preimplantation genetic diagnosis


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