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Bint S.M.,GSTS Pathology | Bint S.M.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | Scriven P.N.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | Scriven P.N.,Kings College London | And 2 more authors.
American Journal of Medical Genetics, Part A

Preimplantation genetic diagnosis (PGD) has been carried out for two couples with different mosaic Robertsonian translocations. Two PGD cycles for a mosaic 13;13 homologous Robertsonian translocation carrier resulted in the birth of a healthy child in each cycle, illustrating the importance of scanning G-banded preparations from homologous Robertsonian carriers for the presence of a normal cell line. One couple was referred for PGD because the male partner carried a mosaic 14;15 Robertsonian translocation with a normal cell line. A single PGD cycle resulted in the birth of a healthy child. Follow-up studies and extended FISH analysis of the carrier's lymphocytes detected three cell lines, two carrying different 14;15 Robertsonian chromosomes and one normal cell line. The two 14;15 Robertsonian chromosomes had different breakpoints in the proximal short arm regions. We suggest that the presence of the D15Z1 polymorphism on the short arm of one chromosome 14 mediated the post-zygotic formation of the two different Robertsonian chromosomes. © 2013 Wiley Periodicals, Inc. Source

Bint S.M.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | MacKie Ogilvie C.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | MacKie Ogilvie C.,Genetics Center | Flinter F.A.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | And 4 more authors.
Human Reproduction

BACKGROUND: The aim of this study was to ascertain the prevalence of meiotic segregation products in embryos from carriers of 13/14 and 14/21 Robertsonian translocations and to estimate the predictive value of testing single cells using the fluorescence in situ hybridization (FISH) technique, to provide more information for decision-making about PGD. Methods In this prospective cohort study, the copy number of translocation chromosomes in nuclei from lysed blastomeres of cleavage-stage embryos was ascertained using locus-specific FISH probes. Logistic regression analysis, controlling for translocation type, female age and fertility status, was used to calculate the odds ratio (OR) of unbalanced segregation products for female and male heterozygotes. The primary diagnostic measure was the predictive value of the test result. The primary outcome measure was the live birth rate per couple. Results Female carriers were four times more likely than male carriers to produce embryos with an unbalanced translocation product (OR 3.8, 95% confidence interval 2.0-7.2, P < 0.001). The prevalence of abnormality for the chromosomes tested in embryos from female or male heterozygotes was estimated to be 43 or 28%, respectively, while estimates of the predictive value were 93-100 or 96-100% for a normal test result and 79 or 57% for an abnormal test result. The live birth rate per couple was 58% for female carriers and 50% for male carriers. CONCLUSIONS For female carriers, PGD using FISH could reduce the risk of miscarriage from either translocation or the risk of Down syndrome from the 14/21 Robertsonian translocation. PGD using FISH for male carriers is unlikely to be indicated given the relatively low prevalence of chromosome imbalance and low predictive value. © The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. Source

Scriven P.N.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | Kirby T.L.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis | Ogilvie C.M.,Guys and St Thomas Center for Preimplantation Genetic Diagnosis
Journal of Visualized Experiments

Pre-implantation genetic diagnosis (PGD) is an established alternative to pre-natal diagnosis, and involves selecting pre-implantation embryos from a cohort generated by assisted reproduction technology (ART). This selection may be required because of familial monogenic disease (e.g. cystic fibrosis), or because one partner carries a chromosome rearrangement (e.g. a two-way reciprocal translocation). PGD is available for couples who have had previous affected children, and/or in the case of chromosome rearrangements, recurrent miscarriages, or infertility. Oocytes aspirated following ovarian stimulation are fertilized by in vitro immersion in semen (IVF) or by intracytoplasmic injection of an individual spermatozoon (ICSI). Pre-implantation cleavage-stage embryos are biopsied, usually by the removal of a single cell on day 3 post-fertilization, and the biopsied cell is tested to establish the genetic status of the embryo. Fluorescence in situ hybridization (FISH) on the fixed nuclei of biopsied cells with target-specific DNA probes is the technique of choice to detect chromosome imbalance associated with chromosome rearrangements, and to select female embryos in families with X-linked disease for which there is no mutation-specific test. FISH has also been used to screen embryos for spontaneous chromosome aneuploidy (also known as PGS or PGD-AS) in order to try and improve the efficiency of assisted reproduction; however, the predictive value of this test using the spreading and FISH technique described here is likely to be unacceptably low in most people's hands and it is not recommended for routine clinical use. We describe the selection of suitable probes for single-cell FISH, spreading techniques for blastomere nuclei, and in situ hybridization and signal scoring, applied to PGD in a clinical setting. Source

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