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Concept: Preimplantation genetic diagnosis


BACKGROUNDGenetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and whole genome sequencing of blastomeres is also expeted to become possible soon. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, will also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues.METHODSThe paper is a joint endeavour by the presenters at an explorative ‘campus meeting’ organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands).RESULTSThe increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. Combinations of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others.CONCLUSIONSAs comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.

Concepts: In vitro fertilisation, Ethics, Assisted reproductive technology, Preimplantation genetic diagnosis, Prenatal diagnosis, Medical genetics, Embryo transfer, Gattaca


Recent advances in stem cells and gene engineering have paved the way for the generation of interspecies chimeras, such as animals bearing an organ from another species. The production of a rat pancreas by a mouse has demonstrated the feasibility of this approach. The next step will be the generation of larger chimeric animals, such as pigs bearing human organs. Because of the dramatic organ shortage for transplantation, the medical needs for such a transgressive practice are indisputable. However, there are serious technical barriers and complex ethical issues that must be discussed and solved before producing human organs in animals. The main ethical issues are the risks of consciousness and of human features in the chimeric animal due to a too high contribution of human cells to the brain, in the first case, or for instance to limbs, in the second. Another critical point concerns the production of human gametes by such chimeric animals. These worst-case scenarios are obviously unacceptable and must be strictly monitored by careful risk assessment, and, if necessary, technically prevented. The public must be associated with this ethical debate. Scientists and physicians have a critical role in explaining the medical needs, the advantages and limits of this potential medical procedure, and the ethical boundaries that must not be trespassed. If these prerequisites are met, acceptance of such a new, borderline medical procedure may prevail, as happened before for in-vitro fertilization or preimplantation genetic diagnosis.

Concepts: Cell, Biology, Pancreas, Animal, Organ, Organ transplant, Human anatomy, Preimplantation genetic diagnosis


Fertility treatment is associated with increased risk of major birth defects, which varies between in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), and is significantly reduced by embryo freezing. We therefore examined a range of additional perinatal outcomes for these exposures.

Concepts: Pregnancy, Reproduction, Infertility, Fertility, In vitro fertilisation, Assisted reproductive technology, Preimplantation genetic diagnosis, Fertility medicine


To preclude transfer of aneuploid embryos, current preimplantation genetic screening (PGS) usually involves one trophectoderm biopsy at blastocyst stage, assumed to represent embryo ploidy. Whether one such biopsy can correctly assess embryo ploidy has recently, however, been questioned.

Concepts: Cell, Embryo, Endometrium, Zygote, Preimplantation genetic diagnosis, Blastocyst, Prenatal diagnosis, Embryo transfer


Noninvasive prenatal testing (NIPT) using sequencing of fetal cell-free DNA from maternal plasma has enabled accurate prenatal diagnosis of aneuploidy and become increasingly accepted in clinical practice. We investigated whether NIPT using semiconductor sequencing platform (SSP) could reliably detect subchromosomal deletions/duplications in women carrying high-risk fetuses. We first showed that increasing concentration of abnormal DNA and sequencing depth improved detection. Subsequently, we analyzed plasma from 1,456 pregnant women to develop a method for estimating fetal DNA concentration based on the size distribution of DNA fragments. Finally, we collected plasma from 1,476 pregnant women with fetal structural abnormalities detected on ultrasound who also underwent an invasive diagnostic procedure. We used SSP of maternal plasma DNA to detect subchromosomal abnormalities and validated our results with array comparative genomic hybridization (aCGH). With 3.5 million reads, SSP detected 56 of 78 (71.8%) subchromosomal abnormalities detected by aCGH. With increased sequencing depth up to 10 million reads and restriction of the size of abnormalities to more than 1 Mb, sensitivity improved to 69 of 73 (94.5%). Of 55 false-positive samples, 35 were caused by deletions/duplications present in maternal DNA, indicating the necessity of a validation test to exclude maternal karyotype abnormalities. This study shows that detection of fetal subchromosomal abnormalities is a viable extension of NIPT based on SSP. Although we focused on the application of cell-free DNA sequencing for NIPT, we believe that this method has broader applications for genetic diagnosis, such as analysis of circulating tumor DNA for detection of cancer.

Concepts: Pregnancy, Infant, Embryo, Fetus, Uterus, Abortion, Preimplantation genetic diagnosis, Triple test


PURPOSE OF REVIEW: To review the foundations, recent technical advances, and increasing number of applications for in-vitro fertilization with preimplantation genetic diagnosis (PGD). RECENT FINDINGS: PGD is an important technique for reducing the burden of genetic disease. Studies have shown that the diagnostic accuracy and subsequent live-birth rate after PGD are impacted by the developmental stage at the time of biopsy, as well as the biopsy protocol used. Also essential for accurate diagnosis are refined mutation detection protocols which avoid the common problem of allele drop-out. As the technique has improved, there has been a concomitant increase in the popularity and breadth of application of PGD. A recently published 10-year dataset of worldwide PGD reveals the increasing frequency of its use and the growing number of indications for which PGD is offered. SUMMARY: Technical advances from biopsy to detection of mutations have led to improved diagnostic accuracy and an increased frequency and breadth of use for PGD.

Concepts: DNA, Genetics, Cancer, Genetic disorder, Mutation, Evolution, In vitro fertilisation, Preimplantation genetic diagnosis


This study aims to evaluate the diagnostic yield of Comparative Genomic Hybridization microarrays (aCGH) and compare it with conventional karyotype analysis of standard >5 Mb resolution.

Concepts: Copy number variation, Cytogenetics, Chromosomes, Aneuploidy, Array comparative genomic hybridization, Preimplantation genetic diagnosis, Metaphase, Prenatal diagnosis


To determine the clinical value of preimplantation genetic diagnosis for aneuploidy screening (PGD-A) in women of advanced maternal age (AMA; between 38 and 41 years).

Concepts: Cancer, Chromosomal translocation, Aneuploidy, Preimplantation genetic diagnosis, Advanced maternal age


The goal was to develop methods for detection of chromosomal and subchromosomal abnormalities in fetal cells in the mother’s circulation at 10-16 weeks gestation using analysis by array comparative genomic hybridization (CGH) and/or next-generation sequencing (NGS).

Concepts: Gene, Pregnancy, Human, Embryo, Uterus, Array comparative genomic hybridization, Preimplantation genetic diagnosis, Metaphase


Preimplantation genetic diagnosis (PGD) aims to test the embryo for specific conditions before implantation in couples at risk of transmitting genetic abnormality to their offspring. The couple must undergo IVF procedures to generate embryos in vitro. The embryos can be biopsied at either the zygote, cleavage or blastocyst stage. Preimplantation genetic screening uses the same technology to screen for chromosome abnormalities in embryos from patients undergoing IVF procedures as a method of embryo selection. Fluorescence in-situ hybridization was originally used for chromosome analysis, but has now been replaced by array comparative genomic hybridization or next generation sequencing. For the diagnosis of single gene defects, polymerase chain reaction is used and has become highly developed; however, single nucleotide polymorphism arrays for karyomapping have recently been introduced. A partnership between IVF laboratories and diagnostic centres is required to carry out PGD and preimplantation genetic screening. Accreditation of PGD diagnostic laboratories is important. Accreditation gives IVF centres an assurance that the diagnostic tests conform to specified standards. ISO 15189 is an international laboratory standard specific for medical laboratories. A requirement for accreditation is to participate in external quality assessment schemes.

Concepts: DNA, Molecular biology, In vitro fertilisation, Assisted reproductive technology, Preimplantation genetic diagnosis, Comparative genomic hybridization, Prenatal diagnosis, Embryo transfer