Conn, Clare Maria; (2002) Molecular cytogenetic analysis of chromosome abnormalities in early human embryos and the development of preimplantation genetic diagnosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Preimplantation genetic diagnosis (PGD) involves the genetic screening of cleavage-stage embryos generated by in vitro fertilisation (IVF), and has been introduced for couples at high risk of transmitting a genetic defect many of whom have experienced recurrent spontaneous or induced abortion. Prompted by growing patient demand, this study has centred on developing new approaches for PGD of chromosomal abnormalities using fluorescent in situ hybridisation (FISH). Dual and triple combinations of locus-specific FISH probes for chromosomes 13, 14, 15, 18 and 21 were developed, and evaluated in seventy-one surplus IVF embryos. In the normally developing group (43 embryos), 67% were uniformly normal, 19% were diploid mosaic, 9% were aneuploid mosaic and 5% were chaotic. In the abnormally developing group (28 embryos), 21% were normal and 79% were chromosomally abnormal. PGD strategies were designed for fifty referrals involving chromosomal indications, 12% of which reached the embryo biopsy stage of PGD whilst 18% are awaiting treatment. Over two thirds withdrew from further treatment, reasons included: 26% losing contact with the Centre, 16% naturally conceived normal pregnancy, 10% electing for alternative treatment, 10% personal circumstances and 8% IVF-related problems. Six couples underwent PGD, one gonadal mosaic for trisomy 21, two balanced reciprocal translocation carriers and three Robertsonian translocation carriers. Over ten IVF cycles, a total of 160 oocytes were retrieved and 72% (53/74) of resulting embryos were biopsied. FISH analysis showed 15% of embryos were normal for the chromosomes tested, whilst 85% were chromosomally unbalanced, categorised as 50% aneuploid/mosaic and 35% chaotic. No clinical pregnancies resulted from three single and three double embryo transfers. From these data three distinct mechanisms were identified which appear to be implicated in the reproductive problems experienced by these patients: gonadal mosaicism with precocious chromatid segregation; increased abnormal meiotic segregation associated with terminal translocation breakpoints; and a high incidence of chaotic chromosome distribution and division in early cleavage-stages.

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