Is the ‘serious’ factor in germline modification really relevant? A response to Kleiderman, Ravitsky and Knoppers

2019 ◽  
Vol 46 (2) ◽  
pp. 151-152 ◽  
Author(s):  
Iñigo De Miguel Beriain
Keyword(s):  
Genetic Testing ◽  
Human Embryos ◽  
Human Beings ◽  
Preimplantation Genetic Testing ◽  
Underlying Factor ◽  
Genome Modification ◽  
Germline Modification ◽  
Serious Disease

Should we use human germline genome modification (HGGM) only when serious diseases are involved? This belief is the underlying factor in the article written by Kleiderman, Ravitsky and Knoppers to which I now respond. In my opinion, the answer to this question should be negative. In this paper, I attempt to show that there are no good reasons to think that this technology should be limited to serious diseases once it is sufficiently proven to be safe and efficient. In fact, opting otherwise would negatively harm human beings’ right to the highest standard of health that unmodified embryos could promote. Therefore, the issue should not be so much to define adequately what a serious disease is, but rather to elucidate whether this concept should play any role beyond the context of preimplantation genetic testing (PGT). This paper argues that we should not accept the similarity between technologies such as PGT and HGGM because they face different challenges and offer totally different possibilities. Therefore, we are in urgent need to build a completely new ethical architecture that covers the application of germline editing in human embryos. As a part of that process, a much deeper debate on the necessity of distinguishing different disease types is required.

scholarly journals Preimplantation Genetic Testing for Chromosomal Abnormalities: Aneuploidy, Mosaicism, and Structural Rearrangements

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 602 ◽  
Author(s):  
Manuel Viotti
Keyword(s):  
Genetic Testing ◽  
Clinical Outcomes ◽  
Assisted Reproductive Technologies ◽  
Chromosomal Abnormalities ◽  
Reproductive Technologies ◽  
Chromosomal Mosaicism ◽  
Human Embryos ◽  
Chromosomal Anomalies ◽  
Structural Rearrangements ◽  
Preimplantation Genetic Testing

There is a high incidence of chromosomal abnormalities in early human embryos, whether they are generated by natural conception or by assisted reproductive technologies (ART). Cells with chromosomal copy number deviations or chromosome structural rearrangements can compromise the viability of embryos; much of the naturally low human fecundity as well as low success rates of ART can be ascribed to these cytogenetic defects. Chromosomal anomalies are also responsible for a large proportion of miscarriages and congenital disorders. There is therefore tremendous value in methods that identify embryos containing chromosomal abnormalities before intrauterine transfer to a patient being treated for infertility—the goal being the exclusion of affected embryos in order to improve clinical outcomes. This is the rationale behind preimplantation genetic testing for aneuploidy (PGT-A) and structural rearrangements (-SR). Contemporary methods are capable of much more than detecting whole chromosome abnormalities (e.g., monosomy/trisomy). Technical enhancements and increased resolution and sensitivity permit the identification of chromosomal mosaicism (embryos containing a mix of normal and abnormal cells), as well as the detection of sub-chromosomal abnormalities such as segmental deletions and duplications. Earlier approaches to screening for chromosomal abnormalities yielded a binary result of normal versus abnormal, but the new refinements in the system call for new categories, each with specific clinical outcomes and nuances for clinical management. This review intends to give an overview of PGT-A and -SR, emphasizing recent advances and areas of active development.

scholarly journals PREIMPLANTATION GENETIC TESTING: Chromosome abnormalities in human embryos

Reproduction ◽  
2020 ◽  
Vol 160 (5) ◽  
pp. A33-A44
Author(s):  
Carmen Rubio ◽  
Lorena Rodrigo ◽  
Carlos Simón
Keyword(s):  
Genetic Testing ◽  
Culture Media ◽  
Sperm Concentration ◽  
Early Embryo ◽  
Chromosome Abnormalities ◽  
Critical Event ◽  
Human Embryos ◽  
Preimplantation Genetic Testing ◽  
Frequent Event

Aneuploidy is a frequent event in human embryos, and its incidence is higher in oocytes and embryos from women of advanced maternal age. Aneuploidy may also be a contributing factor in infertile populations, such as couples with recurrent miscarriages, repetitive implantation failure, or male infertility. For these reasons, preimplantation genetic testing for aneuploidy (PGT-A) has been proposed to prevent miscarriages and increase live birth rates in infertile couples undergoing in vitro fertilisation. Next-generation sequencing is currently being applied for the detection of aneuploidies in human embryos, including whole chromosome aneuploidies, segmental aneuploidies, uniform, and mosaic aneuploidies. More recently, this technology has been incorporated for the analysis of the cell-free DNA secreted by the embryo to the culture media. Chromosome abnormalities mostly originate in female meiosis. Recombination between homologous chromosomes is a critical event that occurs in the foetal ovary. The importance of altered recombination pertains to paternally as well as maternally derived trisomies, but as most aneuploidy arises during oogenesis, the female is at greater risk. For males, sperm concentration is associated with a higher risk of aneuploid sperm and thus aneuploid embryos. Mitosis errors can occur at all stages of early embryo development that result in chromosomally distinct cell populations. The clinical impact of mosaicism depends on the mosaicism type, location, and number of aneuploid cells. Transfer of mosaic embryos has been proposed when no euploid embryos are available in the PGT-A cycle.

scholarly journals Preimplantation Genetic Testing Prevented Intergenerational Transmission of X-Linked Alport Syndrome

2021 ◽  
pp. 1-7
Author(s):  
Xiaoling Hu ◽  
Jiahui Zhang ◽  
Yuan Lv ◽  
Xijing Chen ◽  
Guofang Feng ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Intergenerational Transmission ◽  
Alport Syndrome ◽  
Human Embryos ◽  
Radical Cure ◽  
Preimplantation Genetic Testing ◽  
Monogenic Disorders ◽  
Targeted Ngs ◽  
Stage Renal Disease

<b><i>Background:</i></b> Alport syndrome (AS) is a hereditary renal basement membrane disease that can lead to end-stage renal disease in young adults. It can be diagnosed by genetic analysis, being mostly caused by mutations in <i>COL4A3</i>, <i>COL­4A4</i>, and <i>COL4A5</i>. To date, there is no radical cure for this disease. <b><i>Objectives:</i></b> The aim of this study was to avoid the transmission of AS within an affected family by selecting healthy embryos for uterine transfer. The embryos were identified by preimplantation genetic testing for monogenic disorders (PGT-M). <b><i>Methods:</i></b> We used next-generation sequencing (NGS) to identify mutations in the proband and his parents. The results of NGS were confirmed by Sanger sequencing. Targeted NGS combined with targeted single-nucleotide polymorphism haplotyping was used for the in vitro identification of <i>COL4A5</i> mutations in human embryos to prevent their intergenerational transmission. <b><i>Results:</i></b> The c.349_359delGGACCTCAAGG and c.360_361insTGC mutations in <i>COL4A5</i> were identified in a family affected by X-linked AS. Whole-genome sequencing by NGS with targeted haplotyping was performed on biopsied trophectoderm cells. A healthy baby was born after transfer of a single freeze-thawed blastocyst. <b><i>Conclusions:</i></b> The use of targeted NGS for identifying diagnostic markers combined with targeted haplotyping is an easy and efficient PGT-M method for preventing intergenerational transmission of AS.

scholarly journals The ‘serious’ factor in germline modification

2019 ◽  
Vol 45 (8) ◽  
pp. 508-513 ◽  
Author(s):  
Erika Kleiderman ◽  
Vardit Ravitsky ◽  
Bartha Maria Knoppers
Keyword(s):  
Human Rights ◽  
Assisted Reproductive Technologies ◽  
Genetic Diseases ◽  
Well Being ◽  
Reproductive Technologies ◽  
Preimplantation Genetic Testing ◽  
Policy Statements ◽  
Germline Modification ◽  
Health And Disease ◽  
Serious Disease

Current advances in assisted reproductive technologies aim to promote the health and well-being of future children. They offer the possibility to select embryos with the greatest potential of being born healthy (eg, preimplantation genetic testing) and may someday correct faulty genes responsible for heritable diseases in the embryo (eg, human germline genome modification (HGGM)). Most laws and policy statements surrounding HGGM refer to the notion of ‘serious’ as a core criterion in determining what genetic diseases should be targeted by these technologies. Yet, this notion remains vague and poorly defined, rendering its application challenging and decision making subjective and arbitrary. By way of background, we begin by briefly presenting two conceptual approaches to ‘health’ and ‘disease’: objectivism (ie, based on biological facts) and constructivism (ie, based on human values). The basic challenge under both is sorting out whether and to what extent social and environmental factors have a role in helping to define what qualifies as a ‘serious’ disease beyond the medical criteria. We then focus on how a human rights framework (eg, right to science and right to the highest attainable health) could integrate the concepts of objectivism and constructivism so as to provide guidance for a more actionable consideration of ‘serious’. Ultimately, it could be argued that a human rights framework, by way of its legally binding nature and its globally accepted norms and values, provides a more universal foundation for discussions of the ethical, legal and social implications of emerging or disruptive technologies.

scholarly journals A Non-invasive Chromosome Screening Strategy for Prioritizing in vitro Fertilization Embryos for Implantation

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Chen ◽  
Qin Sun ◽  
Juanjuan Xu ◽  
Haiyan Fu ◽  
Yuxiu Liu ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Predictive Value ◽  
Large Scale ◽  
Human Embryos ◽  
Clinical Practices ◽  
Preimplantation Genetic Testing ◽  
Invasive Approach ◽  
Vitro Fertilization ◽  
Non Invasive

Preimplantation genetic testing for aneuploidy (PGT-A) is widely used to select embryos having normal ploidy for transfer, but they require an invasive embryo biopsy procedure that may cause harm to the embryos and offspring. Therefore, a non-invasive approach to select embryos with normal ploidy for implantation is highly demanded. Non-invasive chromosome screening (NICS) methods have been proposed and applied in clinical practices, but a large-scale validation versus invasive preimplantation genetic testing (PGT) and the whole embryo ploidy has not yet been reported. In this study, by using the whole embryo as a gold standard, we validated NICS assay in a total of 265 donated human embryos and compared its performance with conventional trophectoderm (TE) biopsy PGT. The NICS assay showed promising performance, which is comparable to PGT-TE [sensitivity: 87.36 versus 89.66%; specificity: 80.28 versus 82.39%; negative predictive value (NPV): 91.2 versus 92.86%; positive predictive value (PPV): 73.08 versus 75.73%]. Additionally, NICS provides a scoring system for prioritizing embryo: embryos can be categorized into three groups with euploid prediction probabilities of 90.0, 27.8, and 72.2% for group euploid (A), aneuploid (B), and multiple abnormal chromosomes (MAC) (C), respectively. When an addition of TE assay is provided as a secondary validation, the accuracy significantly increases from 72.2 to 84.3% for group B and from 27.8 to 83.3% for group C. Our results suggest that NICS is a good rule in assay for identifying chromosomal normal embryos for transfer and might serve as a non-invasive approach for prioritizing embryos instead of preventing transfer of aneuploid and MAC embryos. It will help to ensure the safety of offspring and efficient utilization of embryos.

scholarly journals The Technological Advances in Embryo Selection and Genetic Testing: A Look Back at the Evolution of Aneuploidy Screening and the Prospects of Non-Invasive PGT

2021 ◽  
Vol 2 (1) ◽  
pp. 26-34
Author(s):  
Channing Burks ◽  
Kristin Van Heertum ◽  
Rachel Weinerman
Keyword(s):  
Genetic Testing ◽  
Subsequent Development ◽  
Embryo Selection ◽  
Human Embryos ◽  
Comparative Genomic ◽  
Aneuploidy Screening ◽  
Preimplantation Genetic Testing ◽  
Blastomere Biopsy ◽  
Non Invasive ◽  
Technological Advances

Since the birth of the first IVF baby, Louise Brown, in 1978, researchers and clinicians have sought ways to improve pregnancy outcomes through embryo selection. In the 1990s, blastomere biopsy and fluorescence in situ hybridization (FISH) were developed in human embryos for the assessment of aneuploidy and translocations. Limitations in the number of chromosomes that could be assayed with FISH lead to the development of comparative genomic hybridization (CGH); however, pregnancy rates overall were not improved. The later development of trophectoderm biopsy with comprehensive chromosome screening (CCS) technologies, as well as the subsequent development of next-generation sequencing (NGS), have shown much greater promise in improving pregnancy and live birth rates. Recently, many studies are focusing on the utilization of non-invasive preimplantation genetic testing (niPGT) in an effort to assess embryo ploidy without exposing embryos to additional interventions.

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