- Email: [email protected]
GENE REGULATORY NETWORK IN THE CONTEXT OF GENOME INSTABILITY IN HUMAN EMBRYO DEVELOPMENT
e6
RBMO VOLUME 39 ISSUE s1 2019
This may become the major source for performing PGT-M in the near future, allowing to offer PGT-M prospectively before the birth of an affected child. The data show significant increase of the PGT-M uptake following ECS, demonstrating the utility for offering PGT-M prospectively to the couples at risk. Keywords: Expanded Carrier Screening (ECS); Preimplantation Genetic Testing for Monogenic Disorders (PGT-M)
doi: 10.1016/j.rbmo.2019.04.022
GENE REGULATORY NETWORK IN THE CONTEXT OF GENOME INSTABILITY IN HUMAN EMBRYO DEVELOPMENT
these single-cell genomic profiles in combination with cell cleavage imaging of the developing embryos, we could deduce the origin of the abnormalities and construct cell lineages. Single-cell gene expression analysis of the same cells, classified the cells according to the embryonic developmental stage, the expression activation of the embryonic genome and disclosed the functional impact of acquired numerical and structural chromosome aberrations on development of the human embryo. Furthermore, the data reveals which genetic anomalies contribute to the epiblast cells in the blastocyst that provide the ectodermal, mesodermal and endodermal cell lineages, the building blocks of our organs. Keywords: Genetic instability; Single-cell
Thierry Voet
genome-plus-transcriptome sequencing; Mosaicism
Laboratory of Reproductive Genetics, Center of Human Genetics, KU Leuven, Leuven 3000, Belgium
doi: 10.1016/j.rbmo.2019.04.023
Genomic instability is common in preimplantation embryos of a variety of species. Up to 80% of human cleavage stage embryos following in vitro fertilization acquire genetic mosaicism, but some may develop to normal individuals after uterine transfer. The causative mechanisms of this chromosome instability as well as the impact of acquired genetic anomalies on embryo development are not understood and remain speculative.
CLINICAL IMPACT OF MATERNAL-EMBRYONIC COMMUNICATION AT IMPLANTATION
Using novel methodologies for single-cell genome-plustranscriptome sequencing (G&T-seq) of all cells of human preimplantation embryos from the fertilized egg to the blastocyst stage, we disclose insight in the gene regulatory network of preimplantation embryo development and how this is impacted by aneuploidy. Single-cell DNA CNV analysis revealed frequent missegregations of whole chromosomes as well as segmental rearrangements in all embryonic cell stages. Using
Carlos Simón, M.D., Ph.D.1,2,3 1 Department
of Obstetrics and Gynecology, University of Valencia, Spain 2 IGENOMIX foundation/INCLIVA, Valencia, Spain 3 Department of Obstetrics and Gynecology, Baylor College of Medicine, TX, USA
The endometrium is a hormonally regulated organ that is non-adhesive to embryos throughout most of the menstrual cycle in humans. Endometrial receptivity refers to a hormone-limited period in which the endometrial tissue acquires a functional and transient ovarian steroid-dependent status allowing blastocyst adhesion. Functional genomic studies of human endometrium in natural cycles have demonstrated that endometrial receptivity is an active process involving up- and down-regulation of hundreds of genes (1). Personalized medicine is a wellaccepted concept in reproductive
medicine except for the endometrial factor that is still neglected. Our group has developed the endometrial receptivity array (ERA) (2), a customized array of 238 genes now performed using Next Generation Sequencing (NGS) coupled to a computational predictor capable of diagnosing the window of endometrial receptivity regardless of its histological appearance (2). The accuracy of the diagnostic tool ERA has been demonstrated to be superior to endometrial histology and results are completely reproducible 29 to 40 months later (3). The aim of this presentation is to demonstrate the diagnostic and therapeutic efficiency of ERA in patients with implantation failure (IF), through personalization of the day of embryo transfer (pET) (4-8). We are conducting an international RCT to investigate the reproductive outcome of infertile women under 38 year (BMI of 18.530 and AFC>8) s in their first IVF/ ICSI cycle with elective blastocyst transfer randomly allocated to be performed in a fresh cycle, after freezing all embryos or after identification of the personalized WOI with the ERA test (pET). According to a preliminary analysis after recruiting 356 patients of the 546 planned, the pET group had a higher pregnancy rate per ET, and a trend to a higher implantation rate and ongoing pregnancy rate (9). Finally, the investigation of endometrial bacterial communities has revealed that the endometrial cavity is not sterile. The presence of a NonLactobacillus-dominated microbiota (NLD)(<90% Lactobacilli) (10) or pathogens responsible for chronic endometritis (11) in infertile patients are associated with decrease reproductive outcome in terms of implantation, pregnancy and live birth rates.
RBMO VOLUME 39 ISSUE s1 2019
This may become the major source for performing PGT-M in the near future, allowing to offer PGT-M prospectively before the birth of an affected child. The data show significant increase of the PGT-M uptake following ECS, demonstrating the utility for offering PGT-M prospectively to the couples at risk. Keywords: Expanded Carrier Screening (ECS); Preimplantation Genetic Testing for Monogenic Disorders (PGT-M)
doi: 10.1016/j.rbmo.2019.04.022
GENE REGULATORY NETWORK IN THE CONTEXT OF GENOME INSTABILITY IN HUMAN EMBRYO DEVELOPMENT
these single-cell genomic profiles in combination with cell cleavage imaging of the developing embryos, we could deduce the origin of the abnormalities and construct cell lineages. Single-cell gene expression analysis of the same cells, classified the cells according to the embryonic developmental stage, the expression activation of the embryonic genome and disclosed the functional impact of acquired numerical and structural chromosome aberrations on development of the human embryo. Furthermore, the data reveals which genetic anomalies contribute to the epiblast cells in the blastocyst that provide the ectodermal, mesodermal and endodermal cell lineages, the building blocks of our organs. Keywords: Genetic instability; Single-cell
Thierry Voet
genome-plus-transcriptome sequencing; Mosaicism
Laboratory of Reproductive Genetics, Center of Human Genetics, KU Leuven, Leuven 3000, Belgium
doi: 10.1016/j.rbmo.2019.04.023
Genomic instability is common in preimplantation embryos of a variety of species. Up to 80% of human cleavage stage embryos following in vitro fertilization acquire genetic mosaicism, but some may develop to normal individuals after uterine transfer. The causative mechanisms of this chromosome instability as well as the impact of acquired genetic anomalies on embryo development are not understood and remain speculative.
CLINICAL IMPACT OF MATERNAL-EMBRYONIC COMMUNICATION AT IMPLANTATION
Using novel methodologies for single-cell genome-plustranscriptome sequencing (G&T-seq) of all cells of human preimplantation embryos from the fertilized egg to the blastocyst stage, we disclose insight in the gene regulatory network of preimplantation embryo development and how this is impacted by aneuploidy. Single-cell DNA CNV analysis revealed frequent missegregations of whole chromosomes as well as segmental rearrangements in all embryonic cell stages. Using
Carlos Simón, M.D., Ph.D.1,2,3 1 Department
of Obstetrics and Gynecology, University of Valencia, Spain 2 IGENOMIX foundation/INCLIVA, Valencia, Spain 3 Department of Obstetrics and Gynecology, Baylor College of Medicine, TX, USA
The endometrium is a hormonally regulated organ that is non-adhesive to embryos throughout most of the menstrual cycle in humans. Endometrial receptivity refers to a hormone-limited period in which the endometrial tissue acquires a functional and transient ovarian steroid-dependent status allowing blastocyst adhesion. Functional genomic studies of human endometrium in natural cycles have demonstrated that endometrial receptivity is an active process involving up- and down-regulation of hundreds of genes (1). Personalized medicine is a wellaccepted concept in reproductive
medicine except for the endometrial factor that is still neglected. Our group has developed the endometrial receptivity array (ERA) (2), a customized array of 238 genes now performed using Next Generation Sequencing (NGS) coupled to a computational predictor capable of diagnosing the window of endometrial receptivity regardless of its histological appearance (2). The accuracy of the diagnostic tool ERA has been demonstrated to be superior to endometrial histology and results are completely reproducible 29 to 40 months later (3). The aim of this presentation is to demonstrate the diagnostic and therapeutic efficiency of ERA in patients with implantation failure (IF), through personalization of the day of embryo transfer (pET) (4-8). We are conducting an international RCT to investigate the reproductive outcome of infertile women under 38 year (BMI of 18.530 and AFC>8) s in their first IVF/ ICSI cycle with elective blastocyst transfer randomly allocated to be performed in a fresh cycle, after freezing all embryos or after identification of the personalized WOI with the ERA test (pET). According to a preliminary analysis after recruiting 356 patients of the 546 planned, the pET group had a higher pregnancy rate per ET, and a trend to a higher implantation rate and ongoing pregnancy rate (9). Finally, the investigation of endometrial bacterial communities has revealed that the endometrial cavity is not sterile. The presence of a NonLactobacillus-dominated microbiota (NLD)(<90% Lactobacilli) (10) or pathogens responsible for chronic endometritis (11) in infertile patients are associated with decrease reproductive outcome in terms of implantation, pregnancy and live birth rates.