title: What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate.
abstract: Preimplantation genetic screening is being scrutinized, as recent randomized clinical trials failed to observe the expected significant increase in live birth rates following fluorescence in situ hybridization (FISH)-based screening. Although these randomized clinical trials are criticized on their design, skills or premature stop, it is generally believed that well-designed and well-executed randomized clinical trials would resolve the debate about the potential benefit of preimplantation genetic screening. Since FISH can analyze only a limited number of chromosomal loci, some of the embryos transferred might be diagnosed as 'normal' but in fact be aneuploid for one or more chromosomes not tested. Hence, genome-wide array comparative genome hybridization screening enabling aneuploidy detection of all chromosomes was thought to be a first step toward a better design. We recently showed array screening indeed enables accurate determination of the copy number state of all chromosomes in a single cell. Surprisingly, however, this genome-wide array screening revealed a much higher frequency and complexity of chromosomal aberrations in early embryos than anticipated, with imbalances in a staggering 90% of all embryos. The mitotic error rate in cleavage stage embryos was proven to be higher than the meiotic aneuploidy rate and as a consequence, the genome of a single blastomere is not representative for the genome of the other cells of the embryo. Hence, potentially viable embryos will be discarded upon screening a single blastomere. This observation provides a biological basis for the failure of the randomized clinical trials to increase baby-take-home rates using FISH on cleavage stage embryos.
authors.affiliation: Center for Human Genetics, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Vanneste
authors.forename: Thierry
authors.initials: T
authors.lastname: Voet
authors.forename: Cindy
authors.initials: C
authors.lastname: Melotte
authors.forename: Sophie
authors.initials: S
authors.lastname: Debrock
authors.forename: Karen
authors.initials: K
authors.lastname: Sermon
authors.forename: Catherine
authors.initials: C
authors.lastname: Staessen
authors.forename: Inge
authors.initials: I
authors.lastname: Liebaers
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Thomas
authors.initials: T
authors.lastname: D'Hooghe
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D000782:Aneuploidy; D001723:Birth Rate; D001755:Blastocyst; D002877:Chromosomes, Human; D005260:Female; D005820:Genetic Testing; D042822:Genomic Instability; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008938:Mitosis; D011247:Pregnancy; D019836:Preimplantation Diagnosis; D016032:Randomized Controlled Trials as Topic