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• W4308406552 abstract "Over the last several decades, driven largely by the Human Genome project and next generation sequencing, Genetics has enriched the field of reproductive medicine. We have gained tremendous insights into the genetic causes of infertility, developed a myriad of genetic screening tools, and have made a substantial headway in human gene editing technology. Genetic technology is here to stay, and will only continue to infiltrate reproductive science. Our field is now faced with the question of how we move forward considering the advancements in the field of Genetics. Do we, as reproductive health care providers, focus on the management of endocrinopathies (RE) or do we shift priorities to focus on disease prevention and elimination through the use of genetic tools (RG)? In reality, genetics is the way of the future, and now is the time to transition the role from reproductive endocrinologist to reproductive geneticist. One of the earliest genetic innovations in our field was the implementation of carrier screening programs in the 1970s (1Kraft S.A. Duenas D. Wilfond B.S. Goddard K.A.B. The evolving landscape of expanded carrier screening: challenges and opportunities.Genet Med. 2019; 21: 790-797Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Although first used as ancestry-based screening for high- risk conditions in various ethnic groups, with the introduction of next generation sequencing, this testing has expanded to include screening for hundreds of pan–ethnic-heritable diseases. When single–gene-heritable conditions are detected in both patients and their partners, preimplantation genetic testing for monogenic disorders (PGT-M), a technology developed in the early 1990s, can be used to screen for and select embryos unaffected by the condition of interest (2Mai A.D. Harton G.L. Quang V.N. Van H.N. Thi N.H. Thuy N.P. et al.Development and clinical application of a preimplantation genetic testing for monogenic disease (PGT-M) for beta thalassemia in Vietnam.J Assist Reprod Genet. 2021; 38: 365-374Crossref PubMed Scopus (5) Google Scholar). A cost-effectiveness analysis was performed comparing natural conception vs. PGT-M in patients heterozygous for the autosomal dominant condition, Huntington’s Disease (HD). In this study, PGT-M was lower in cost and higher in effectiveness at preventing HD-affected offspring than in natural conception (3Christensen A.A. Parker P.B. Hersh A.R. Caughey A.B. Krieg S.A. In vitro fertilization with preimplantation genetic testing for monogenetic diseases versus unassisted conception with prenatal diagnosis for Huntington disease: a cost-effectiveness analysis.Fertil Steril. 2022; 118: 56-64Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). Although the reproductive endocrinologists of the past were taught how to manage many heritable endocrinopathies, like congenital adrenal hyperplasia and Fragile X, advancement in genetics through PGT-M technology and the widespread universal carrier screening, may allow us to essentially eliminate these conditions by selecting for and transferring the unaffected embryos. Since then, PGT technology has expanded to include embryo testing for aneuploidy (PGT-A) and structural rearrangements (PGT-SR). With the development of PGT-A platforms, we are now able to overcome the leading genetic cause of reproductive failure, chromosomal aneuploidy, and optimize live birth rate by selecting euploid embryos for transfer. PGT-A has been associated with an improvement in live birth rate in women of advanced maternal age, and recent randomized control trials have also demonstrated an improvement in the ongoing pregnancy rates with PGT-A testing compared with the transfer of untested embryos across all age groups (4Rubio C. Bellver J. Rodrigo L. Castillón G. Guillén A. Vidal C. et al.In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study.Fertil Steril. 2017; 107: 1122-1129Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 5Sacchi L. Albani E. Cesana A. Smeraldi A. Parini V. Fabiani M. et al.Preimplantation genetic testing for aneuploidy improves clinical, gestational, and neonatal outcomes in advanced maternal age patients without compromising cumulative live-birth rate.J Assist Reprod Genet. 2019; 36: 2493-2504Crossref PubMed Scopus (32) Google Scholar, 6Greco E. Litwicka K. Minasi M.G. Cursio E. Greco P.F. Barillari P. Preimplantation genetic testing: where we are today.Int J Mol Sci. 2020; 21: 4381Crossref Scopus (21) Google Scholar, 7Yang Z. Liu J. Collins G.S. Salem S.A. Liu X. Lyle S.S. et al.Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study.Mol Cytogenet. 2012; 5: 24Crossref PubMed Scopus (240) Google Scholar, 8Scott Jr., R.T. Upham K.M. Forman E.J. Hong K.H. Scott K.L. Taylor D. et al.Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial.Fertil Steril. 2013; 100: 697-703Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar). For patients found to be reciprocal translocation carriers after workup for recurrent pregnancy loss, the use of PGT technology for PGT-SR improves live birth rates and decreases miscarriage rates (9Huang C. Jiang W. Zhu Y. Li H. Lu J. Yan J. et al.Pregnancy outcomes of reciprocal translocation carriers with two or more unfavorable pregnancy histories: before and after preimplantation genetic testing.J Assist Reprod Genet. 2019; 36: 2325-2331Crossref PubMed Scopus (19) Google Scholar). Although still an investigational tool, preimplantation genetic testing for polygenic disorders (PGT-P), may allow for the selection of embryos that have the greatest chance of resulting in healthy offspring. In addition, PGT-P assesses the genetic variants present within the genome of a blastocyst embryo after trophectoderm biopsy. This genetic information is computed into a polygenic risk score that can be used to estimate a given embryo’s genetic susceptibility to conditions such as cardiovascular disease, cancer, and diabetes (10Siermann M. Tšuiko O. Vermeesch J.R. Raivio T. Borry P. A review of normative documents on preimplantation genetic testing: recommendations for PGT-P.Genet Med. 2022; 24: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). Additionally, genome wide association studies (GWAS) have allowed us to uncover previously unknown genetic associations with infertility. Through these studies we have identified mutations in FMR1 gene, FOXL2, and GLAT genes, which have been associated with primary ovarian insufficiency (11Ruth K.S. Day F.R. Hussain J. Martínez-Marchal A. Aiken C.E. Azad A. et al.Genetic insights into biological mechanisms governing human ovarian ageing.Nature. 2021; 596: 393-397Crossref PubMed Scopus (47) Google Scholar). However, the investigation continues with the goal of identifying rarer genetic etiologies of infertility. Several single nucleotide polymorphisms have been identified in association with the CDKN2B-AS gene and thought to contribute to the dysregulation of cell growth within the endometrium, leading to the development of endometriosis and infertility (12Pisarska M.D. Chan J.L. Lawrenson K. Gonzalez T.L. Wang E.T. Genetics and epigenetics of infertility and treatments on outcomes.J Clin Endocrinol Metab. 2019; 104: 1871-1886Crossref PubMed Scopus (29) Google Scholar). Multiple risk associations close to the LHCGR gene, which encodes luteinizing hormone and human chorionic gonadotropin receptors, have been identified in GWASs for patients with polycystic ovary syndrome (PCOS), and may impact appropriate hormonal regulation during the menstrual cycle (13McAllister J.M. Legro R.S. Modi B.P. Strauss 3rd, J.F. Functional genomics of PCOS: from GWAS to molecular mechanisms.Trends Endocrinol Metab. 2015; 26: 118-124Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). Oocyte maturation, fertilization, and early embryonic development are regulated by a series of genetic and metabolic events. Mutations in the PATL2, TUBB8, TRIP13, and PANX1 genes have been identified through genetic studies and are all implicated in oocyte maturation arrest (14Jiao S.Y. Yang Y.H. Chen S.R. Molecular genetics of infertility: loss-of-function mutations in humans and corresponding knockout/mutated mice.Hum Reprod Update. 2021; 27: 154-189Crossref PubMed Scopus (56) Google Scholar). Mutations in human zona pellucida glycoproteins lead to the development of abnormal oocytes with zona pellucida defects and impaired fertilization, and mutations in WEE2 have been linked to total fertilization failure (15Dai J. Zheng W. Dai C. Guo J. Lu C. Gong F. et al.New biallelic mutations in WEE2: expanding the spectrum of mutations that cause fertilization failure or poor fertilization.Fertil Steril. 2019; 111: 510-518Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). One study pioneered the injection of WEE2 coding RNA into affected oocytes before intracytoplasmic sperm injection that rescued the fertilization failure phenotype and allowed for formation of blastocysts (16Sang Q. Li B. Kuang Y. Wang X. Zhang Z. Chen B. et al.Homozygous mutations in WEE2 cause fertilization failure and female infertility.Am J Hum Genet. 2018; 102: 649-657Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Certainly, additional genetic mutations responsible for fertilization failure remain to be discovered, and the door is open for novel therapeutic treatment options targeting the genetic causes of infertility. Established causes of male infertility with genetic origins include azoospermia or oligozoospermia, asthenozoospermia, and teratozoospermia. Mutations in the cystic fibrosis (CFTR) gene and congenital bilateral absence of the vas deferens, Y chromosome microdeletions, and chromosomal conditions, such as Klinefelter syndrome, are well known causes of male infertility. Yet most of the cases of nonobstructive azoospermia remain idiopathic; there is a long list of candidate gene mutations implicated, including genes targeting meiosis, chromatid body function, cell cycle, histone-to-protamine exchange, enzymatic activity, and transcription factors. However, given the large number of genes essential for normal spermatogenesis, each gene may be responsible for a fraction of cases, and continued research using advanced sequencing technology is warranted. Gene mutations identified to cause asthenozoospermia via multiple morphologic abnormalities of the sperm flagella include mutations in the dynein axonemal heavy chain family (DNAH) (DNAH1, DNAH2, DNAH6, DNAH17), cilia and flagella associated protein family (CFAP) (CFAP43/33, CFAP65, CFAP69, CFAP 70, CFAP251), fibrous sheath interacting protein 2 (FSIP2), tetratricopeptide repeat domain (TCC) (TCC21A, TCC29), and sperm flagellar 2 (SPEF2) (17Nsota Mbango J.F. Coutton C. Arnoult C. Ray P.F. Touré A. Genetic causes of male infertility: snapshot on morphological abnormalities of the sperm flagellum.Basic Clin Androl. 2019; 29: 2Crossref PubMed Scopus (31) Google Scholar). These genes are distinct from genes implicated in primary ciliary dyskinesia, indicating the high genetic heterogeneity of the asthenozoospermia phenotype. Novel genetic findings will continue to provide genotype-phenotype correlations and improve the diagnosis efficiency of male infertility. Research is emerging that focuses on the relationship between epigenetics and infertility. Epigenetic modifications do not alter the DNA sequences, but change the chromatin structure and DNA accessibility through DNA methylation and non-coding regulatory elements, which subsequently alters the gene expression. Aberrations in sperm DNA methylation have been implicated in impaired spermatogenesis and fertilization and sperm non-coding RNAs may play a role in early zygotic development (18Salas-Huetos A. Aston K.I. Defining new genetic etiologies of male infertility: progress and future prospects.Transl Androl Urol. 2021; 10: 1486-1498Crossref PubMed Scopus (5) Google Scholar). Epigenetic modifications play a role in reproductive aging with altered DNA methyltransferase regulation, DNA methylation levels, and histone acetylation as well as methylation patterns noted in the oocytes of patients with advanced maternal age (19Chamani I.J. Keefe D.L. Epigenetics and female reproductive aging.Front Endocrinol (Lausanne). 2019; 10: 473Crossref PubMed Google Scholar). In discovering DNA methylation and histone acetylation patterns associated with infertility, epigenetic modifications may be used in the future to improve outcomes. Although genetic screening through the previously described platforms has limitations and cannot completely prevent disease, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR-Cas9) and further refined technology may allow for genomic modification of human heritable disorders in the future. CRISPR, clustered regularly interspaced palindromic repeats with CRISPR-associated protein 9 (Cas9), target nucleic acids and induce site specific DNA cleavage to modify genes (20Kato-Inui T. Takahashi G. Hsu S. Miyaoka Y. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 with improved proof-reading enhances homology-directed repair.Nucleic Acids Res. 2018; 46: 4677-4688Crossref PubMed Scopus (40) Google Scholar). Microinjection of Cas9 can be applied to developing zygotes, or even oocytes, to induce genetic modification. The CRISPR-Cas9 technology has been applied to human embryos and was proven to successfully correct a genetic mutation in the human MYBPC3 gene, the single gene associated with hypertrophic cardiomyopathy (mutant autosomal allele delta GAGT) (21Mosqueira D. Mannhardt I. Bhagwan J.R. Lis-Slimak K. Katili P. Scott E. et al.CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy.Eur Heart J. 2018; 39: 3879-3892Crossref PubMed Scopus (110) Google Scholar). We have only just scratched the surface of how genetic tools will change and drive our field. In the not too distant future we may be able to offer our patients individualized whole genome sequencing, and intervene with fertility preservation if mutations associated with primary ovarian insufficiency or certain cancers are detected. Half of our patients with infertility are estimated to have a genetic component; next generation sequencing will continue to facilitate the characterization of infertility-associated gene mutations (11Ruth K.S. Day F.R. Hussain J. Martínez-Marchal A. Aiken C.E. Azad A. et al.Genetic insights into biological mechanisms governing human ovarian ageing.Nature. 2021; 596: 393-397Crossref PubMed Scopus (47) Google Scholar). It is imperative that we, as reproductive specialists, understand the indications for and limitations of genetic technologies if we are to recommend these tests to our patients. It is crucial for us to appreciate the differences between various genetic testing platforms and how to interpret results. We must know the benefits and limitations to various preimplantation genetic testing platforms that include quantitative polymerase chain reaction, array comparative genomic hybridization, single nucleotide polymorphism array and next generation sequencing. When PGT-M is being used for monogenic but multiallelic disorders, allelic dropout during polymerase chain reaction based target sequencing may lead to increased false-negative diagnoses for rare variants. How do we counsel our patients on the sensitivity and specificity of these tools? How do we explain the reproductive potential of mosaic embryos? How do we counsel patients on the variants of unknown significance discovered during carrier screening? As reproductive specialists, we must understand the mechanics of the genetic tools that we are offering. Our future reproductive health now lies on genetics and the use of genetic innovations and tools. If we as reproductive specialists do not become reproductive geneticists, our role in the field may be lost. Our endocrine colleagues confidently manage our patients with PCOS and Turner’s syndrome, and reproductive surgery is largely performed by minimally invasive trained gynecologists. Referrals for Mullerian anomalies are frequently funneled to pediatric endocrinologists and pediatric and adolescent gynecologists. Procedures that used to be exclusively performed by Reproductive Endocrinology and Infertility (REI) trained physicians, like oocyte retrievals and embryo transfers, are now being performed by generalist obstetricians and gynecologists. We have a tremendous opportunity to individualize and better care for our patients through the use of genetic technology; however, it is paramount that we understand the depth and breadth of reproductive genetics. Progress has made new discoveries in the endocrinology of assisted reproductive technology obsolete; the new insights will come from genetics. My first uncensored thoughts when tapped to defend this side of the debate are as follows: a subspecialist in REI who lacks the endocrinology training and becomes a reproductive geneticist and infertility provider is nothing more than a trained dog who has been taught to retrieve eggs and fetch embryos for transfer that his master has selected for him. Always beholden to his master and largely ignorant of the tools and methods behind the selection of embryos; he follows their lead in what to fetch and retrieve. Like that dog or at least the many Labrador Retrievers I have owned, he will never tire of this task and will salivate over the immodest financial bone he earns from it. This gap in understanding of the science behind the practice will only increase when designer embryos are CRISPR-Cas’ed 9 to perfection, but the financial rewards proportional to the amount of technology invested in the treatment will only increase, strengthening the dog-master bond. Hounds of the world unite, you have nothing to lose but your chains. You need to control the means of production. What is it that only the subspecialist in REI can produce that makes this provider essential? It is certainly not genetic or even assisted reproductive technology procedure expertise. We are seeing obstetricians and gynecologists (and really why not anyone with a valid medical license) hired by corporate infertility practices to assume the roles of REI subspecialists. In other countries, for instance the United Kingdom, nurse practitioners at some National Heatlh Service fertility programs are performing the oocyte retrievals and embryo transfers (although guided by M.D. specialists in ovarian stimulation cycle management). Clinical care that involves carrier screening, whole genome screening for undiagnosed diseases, PGT of embryos in all its flavors relies almost exclusively on results from commercial genomic companies that provide reports and interpretations back to the provider (note: any provider can order such a test) as well as often providing genetic counseling to the patient easing our understaffed academic units. We are merely messengers when it comes to the human genome in Reproductive Medicine. In a nutshell what reproductive endocrinologists provide is their knowledge and wisdom in the field of reproductive endocrinology. Does a geneticist treat infertility in a patient with Kallmann’s Syndrome with a FGF8 mutation or a patient with Turner’s Mosaicism or one with cystic fibrosis? Does a geneticist treat a woman who faces a lifetime of sequelae from PCOS or primary ovarian insufficiency? Of course not. What defines the reproductive endocrinologist is their clinical expertise in the field coupled with the acquired scientific prowess and skepticism to judiciously select next generation diagnostic tests and treatments on the basis of evidence (please note the importance of the research during fellowship to develop this latter skill of scientific skepticism). The American Board of Obstetricians and Gynecologists begins its definition of a REI subspecialist as follows: “An REI subspecialist is an obstetrician or gynecologist who provides consultation and/or comprehensive care for women with complex problems related to REI (22American Board of Obstetrics and GynecologyGuide to learning in reproductive endocrinology and infertility.https://www.abog.org/docs/default-source/guides-to-learning-library/guides-to-learning/guide-to-learning-rei-2018.pdf?sfvrsn=15771dab_0Date accessed: September 26, 2022Google Scholar).” Let me summarize this. It is only through the mastery of endocrinology, not genetics, that an REI can provide complex and comprehensive care to patients with disorders related to reproductive failure. Required clinical training has expanded and is now named “REI Core Clinical Experience” and includes the following domains: Basic Science, Physiology, and Pathophysiology, Diagnostic Techniques and Interpretation for the Management of Reproductive Disorders, Evaluation, Diagnosis, and Management of Reproductive Endocrine Function and Disease, Female Fertility, Female Infertility, and PCOS, Male Infertility, Recurrent Pregnancy Loss, Assisted Reproductive Technology Techniques Evaluation, Diagnosis, and Management of Complex Reproductive Disorders, Complex Reproductive Surgical Procedures, and Genetics. Please note genetics is a component of the required knowledge, almost an afterthought, but subsumed by the much broader requirement for medical and surgical training. It is the ability to think and integrate a variety of data and make complex decisions and/or perform complex surgery (oocyte retrievals and embryo transfers are not complex surgery), not parrot recommendations from genetic vendors, that make a reproductive endocrinologist invaluable. We have overestimated and overused the fruits of the Human Genome project in the practice of reproductive medicine. The Human Genome project has provided many breakthroughs. It has unraveled the human phenotypes of rare mendelian disorders such as aromatase deficiency, isolated follicle-stimulating hormone deficiency or inactivating mutations of the kisspeptin receptor. Most of us will never see a case related to these single gene defects in our professional lifetimes. These are often disorders that result in severe phenotypes, such as delayed puberty or primary amenorrhea and statistically make up only a small portion of such cases. The diagnosis and management of the complex causes, genetic and acquired, of delayed puberty and primary amenorrhea are within the scope of practice of a reproductive endocrinologist, again, not that of a geneticist. For complex genetic diseases infinitely more common in our waiting rooms, the Human Genome project has allowed for the identification of genetic variants associated with the reproductive disorders. Extensive GWASs performed by multiple investigative groups have been performed for disorders with familial clustering such as PCOS (23Shi Y. Zhao H. Shi Y. Cao Y. Yang D. Li Z. et al.Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome.Nat Genet. 2012; 44: 1020-1025Crossref PubMed Scopus (408) Google Scholar, 24Hayes M.G. Urbanek M. Ehrmann D.A. Armstrong L.L. Lee J.Y. Sisk R. et al.Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.Nat Commun. 2015; 6: 7502Crossref PubMed Scopus (221) Google Scholar) and endometriosis (25Gallagher C.S. Makinen N. Harris H.R. Rahmioglu N. Uimari O. Cook J.P. et al.Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.Nat Commun. 2019; 10: 4857Crossref PubMed Scopus (47) Google Scholar, 26Nyholt D.R. Low S.K. Anderson C.A. Painter J. Uno S. Morris A. et al.Genome-wide association meta-analysis identifies new endometriosis risk loci.Nat Genet. 2012; 44: 1355-1359Crossref PubMed Scopus (223) Google Scholar). However, the results, at least in terms of changing clinical practice or even deepening our understanding of the etiology of the disorder, have been disappointing. Genetically, in most cases each of the significant variants discovered have a small, if not miniscule, contribution to the disorder and in combination they still explain only a minority of the genetic contribution. Functional studies which attempt to identify the pathophysiology of a specific variant to the disorder are either not rigorously pursued given the number of variants identified (which only increase when meta-analyses of GWASs are performed and new variants reach statistical significance through the power of a large sample size) may lead to potential mechanisms (27McAllister J.M. Modi B. Miller B.A. Biegler J. Bruggeman R. Legro R.S. et al.Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype.Proc Natl Acad Sci U S A. 2014; 111: E1519-E1527Crossref PubMed Scopus (151) Google Scholar), but very rarely to immediate clinical utility. More commonly, I suspect, such studies fizzle out and do not see the light of publication. I am not aware of any GWAS–identified-gene variants in PCOS or endometriosis that have contributed to an approved diagnostic test or treatment that has advanced patient care. No one is more disappointed about this than me because I have devoted a good portion of my research career to understanding the genetic underpinnings of PCOS and am still scratching my head 30 years down the road why these studies have not found more. I am reminded of an interaction with the eminent and now deceased reproductive endocrinologist, Dr. Paul McDonough from Medical College of Georgia, who told me 30 years ago in his inimitable way that I was wasting my time looking for PCOS genes as it was both a heterogeneous and complex disorder. RIP Dr. McDonough. Personally I do not regret the journey as it led me—like many journeys—back to the beginning, i.e., the best delivery of care in reproductive endocrinology. I also do not recall Dr. McDonough or any of his eminent trainees (including the now retired former CEO of American Society for Reproductive Medicine, Dr. Richard Reindollar) ever claiming to be reproductive geneticists, but all were proud to be card-carrying reproductive endocrinologists. However, pundits can argue that the Human Genome project has led to a variety of genetic tests transforming clinical care, such as the current gold standard of next generation sequencing, allowing us to screen embryos for genetic abnormalities. (Let us just skip over preimplantation genetic screening of blastomeres from cleavage stage embryos with fluorescence in situ hybridization) (28Mastenbroek S. Twisk M. van Echten-Arends J. Sikkema-Raddatz B. Korevaar J.C. Verhoeve H.R. et al.In vitro fertilization with preimplantation genetic screening.N Engl J Med. 2007; 357: 9-17Crossref PubMed Scopus (570) Google Scholar). However, the benefits of routine embryo biopsy and genetic testing, whether the source are blastomeres or trophectoderm cells by PGT-A from the blastocyst remain elusive—more braggadocio than scientific fact. Some would argue that it is the profit motive driving the use of PGT-A, given that PGT-A is an add on and often an out of pocket expense even for those with infertility coverage. Perhaps PGT-A may result in a shorter time to pregnancy and live birth, perhaps a low chance of miscarriage, but also perhaps a low per cycle live birth rate. Results of large multicenter trials of PGT-A do not support its routine use (29Munné S. Kaplan B. Frattarelli J.L. Child T. Nakhuda G. Shamma F.N. et al.Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial.Fertil Steril. 2019; 112 (1071–9.e7)Abstract Full Text Full Text PDF Scopus (239) Google Scholar, 30Yan J. Qin Y. Zhao H. Sun Y. Gong F. Li R. et al.Live birth with or without preimplantation genetic testing for aneuploidy.N Engl J Med. 2021; 385: 2047-2058Crossref PubMed Scopus (40) Google Scholar). Moreover, we still lack fundamental knowledge about the fate of abnormal biopsy results because we do not know to what extent mosaicism in trophoectoderm reflects that of the inner cell mass or to what extent aneuploidy may resolve over the course of pregnancy or remain sequestered in isolated pockets of the placenta, and thus it may be part of a normal embryo development. The successful live birth, resulting in infants without genetic abnormalities after the transfer of mosaic embryos, heightens this conundrum as do the relatively modest decreases in pregnancy loss that follow transfer of euploid blastocysts. Of course, it is only a matter of time before aneuploid embryos are transferred. We have certainly seen providers in our realm exceeding the moral bounds when it comes to an excessive number of embryos transferred, genetic manipulation of gametes and embryos, excessive use of oocyte donors, and excessive age of recipients of donor oocytes. Perhaps an intermediary state of evolution from the reproductive endocrinologist to the reproductive geneticist should be the reproductive ethicist. We have accepted the print outs from PGT-A testing as gospel without questioning the limitations of the test. In an unselected population, PGT-A remains a screening test and not a diagnostic test. A lesson can be learned from the use of cell free DNA to perform noninvasive pregnancy testing. Although the sensitivity a" @default.
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