title: Meiotic outcomes of three-way translocations ascertained in cleavage-stage embryos: refinement of reproductive risks and implications for PGD.
abstract: Our study provides an analysis of the outcome of meiotic segregation of three-way translocations in cleavage-stage embryos and the accuracy and limitations of preimplantation genetic diagnosis (PGD) using the fluorescence in situ hybridization technique. We propose a general model for estimating reproductive risks for carriers of this class of complex chromosome rearrangement. The data presented describe six cycles for four couples where one partner has a three-way translocation. For male heterozygotes, 27.6% of embryos were consistent with 3:3 alternate segregation resulting in a normal or balanced translocation chromosome complement; 41.4% were consistent with 3:3 adjacent segregation of the translocations, comprising 6.9% reflecting adjacent-1 and 34.5% adjacent-2 segregation; 24.1% were consistent with 4:2 nondisjunction; none showed 5:1 or 6:0 segregation; the probable mode could not be ascertained for 6.9% of embryos due to complex mosaicism or nucleus fragmentation. The test accuracy for male heterozygotes was estimated to be 93.1% with 100% sensitivity and 75% specificity. With 72.4% prevalence, the predictive value was estimated to be 91.3% for an abnormal test result and 100% for a normal test result. Two of four couples had a healthy baby following PGD. The proportion of normal/balanced embryo could be significantly less for female heterozygotes, and our model indicates that this could be detrimental to the effectiveness of PGD. A 20% risk of live-born offspring with an unbalanced translocation is generally accepted, largely based on the obstetric history of female heterozygotes; we suggest that a 3% risk may be more appropriate for male carriers.
authors.affiliation: 1] Guy's & St Thomas' Centre for PGD, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK [2] Division of Genetics & Molecular Medicine, King's College London, School of Medicine at Guy's, King's College & St Thomas' Hospitals, London, UK.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Scriven
authors.affiliation: 1] Guy's & St Thomas' Centre for PGD, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK [2] Cytogenetics department, GSTS-Pathology, Guy's & St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Bint
authors.affiliation: 1] Guy's & St Thomas' Centre for PGD, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK [2] Cytogenetics department, GSTS-Pathology, Guy's & St. Thomas' NHS Foundation Trust, London, UK.
authors.forename: Angela F
authors.initials: AF
authors.lastname: Davies
authors.affiliation: 1] Guy's & St Thomas' Centre for PGD, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK [2] Division of Genetics & Molecular Medicine, King's College London, School of Medicine at Guy's, King's College & St Thomas' Hospitals, London, UK [3] Genetics Centre, Guy's & St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Caroline Mackie
authors.initials: CM
authors.lastname: Ogilvie
mesh_terms: D000328:Adult; D020090:Chromosome Segregation; D002970:Cleavage Stage, Ovum / Q000166:cytology / Q000378:metabolism*; D004624:Embryo Transfer / Q000379:methods; D005260:Female; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D059785:Karyotype; D008297:Male; D008540:Meiosis / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D011247:Pregnancy; D019836:Preimplantation Diagnosis / Q000379:methods / Q000706:statistics & numerical data; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012307:Risk Factors; D014178:Translocation, Genetic