Preimplantation Genetic Diagnosis Research Articles

Successful pregnancy in a complex chromosomal rearrangement carrier using preimplantation genetic testing for structural rearrangements: A case report.

Complex chromosomal rearrangements (CCRs) frequently lead to unfavorable reproductive consequences, such as recurrent miscarriage. Preimplantation genetic testing for structural rearrangements (PGT-SR) has become a successful method for embryo diagnosis in CCR families. A woman of childbearing age experienced repeated miscarriages during her attempts to conceive. A woman was diagnosed with a combined Robertsonian translocation involving chromosomes 13 and 15 (robs[13;15]) and a reciprocal translocation involving chromosomes 10 and 12 (t[10;12]). She had undergone 5 previous embryonic terminations. The couple underwent assisted reproductive technology with ovulation induction using a high-progesterone progestin-primed ovarian stimulation protocol, followed by intracytoplasmic sperm injection and blastocyst culture. Embryo biopsy was carried out on days 5 and 6, and PGT-SR was employed for genetic diagnosis. After aneuploidy detection by PGT-SR, the sole remaining blastocyst underwent preimplantation genetic testing for aneuploidy for confirmation and subsequent transfer. Prenatal diagnosis and follow-up after birth were conducted. For CCR carriers, particularly couples with a history of recurrent abortion, PGT-SR has the potential to address their reproductive predicament by enhancing their likelihood of achieving a successful pregnancy.

Could metabolic imaging and artificial intelligence provide a novel path to non-invasive aneuploidy assessments? A certain clinical need.

Pre-implantation genetic testing for aneuploidy (PGT-A) via embryo biopsy helps in embryo selection by assessing embryo ploidy. However, clinical practice needs to consider the invasive nature of embryo biopsy, potential mosaicism, and inaccurate representation of the entire embryo. This creates a significant clinical need for improved diagnostic practices that do not harm embryos or raise treatment costs. Consequently, there has been an increasing focus on developing non-invasive technologies to enhance embryo selection. Such innovations include non-invasive PGT-A, artificial intelligence (AI) algorithms, and non-invasive metabolic imaging. The latter measures cellular metabolism through autofluorescence of metabolic cofactors. Notably, hyperspectral microscopy and fluorescence lifetime imaging microscopy (FLIM) have revealed unique metabolic activity signatures in aneuploid embryos and human fibroblasts. These methods have demonstrated high accuracy in distinguishing between euploid and aneuploid embryos. Thus, this review discusses the clinical challenges associated with PGT-A and emphasizes the need for novel solutions such as metabolic imaging. Additionally, it explores how aneuploidy affects cell behaviour and metabolism, offering an opinion perspective on future research directions in this field of research.

Navigating Hope and Complexity: Turkish Parents' Experiences with Savior Siblings.

Preimplantation genetic diagnosis (PGD) with human leukocyte antigen (HLA) typing represents a significant advancement in treating inherited hematological disorders, particularly thalassemia major. This technology enables the birth of healthy children who can serve as compatible stem cell donors for their affected siblings. Turkey is a world leader in both PGD+HLA typing technology and hematopoietic stem cell transplantation from savior siblings born through PGD+HLA typing. This study investigated the experiences of Turkish parents who underwent successful savior sibling procedures using preimplantation genetic diagnosis (PGD) with human leukocyte antigen (HLA) typing and then successful hematopoietic stem cell transplantation, from this savior sibling, for the treatment of their thalassemia major child. The research aimed to understand the medical, psychological, and socio-cultural dimensions of this complex process within the Turkish healthcare context. A qualitative study using descriptive phenomenological approach was conducted. In-depth interviews were performed with 16 parents, who successfully completed PGD+HLA matching and subsequent successful stem cell transplantation process from this savior sibling to their thalassemia child. Data were analyzed using Colaizzi's seven-step method and MAXQDA 20.0 software. Analysis revealed six main themes: Disease Stage, Treatment, Recovery Process, Social Family, Support Systems, and Recommendations. Parents reported significant emotional challenges but demonstrated unexpected resilience. Religious and cultural factors played nuanced roles, with most parents viewing the process as compatible with their beliefs. Economic burden, prolonged hospitalizations, and geographical access to treatment centers emerged as key challenges. Extended family support and healthcare professional guidance were identified as crucial support mechanisms. The study highlights the complex interplay between advanced medical technologies and traditional values in Turkish society. Findings emphasize the need for comprehensive, culturally sensitive support systems and long-term follow-up for families. Results suggest implementing multidisciplinary care teams and developing specialized support programs for families undergoing savior sibling procedures.

Unlocking a Decade of Research on Embryo-Derived Extracellular Vesicles: Discoveries Made and Paths Ahead.

Over the past decade, research on embryo-derived extracellular vesicles (EVs) has unveiled their critical roles in embryonic development and intercellular communication. EVs secreted by embryos are nanoscale lipid bilayer vesicles that carry bioactive cargo, including proteins, lipids, RNAs, and DNAs, reflecting the physiological state of the source cells. These vesicles facilitate paracrine and autocrine signaling, influencing key processes such as cell differentiation, embryo viability, and endometrial receptivity. Studies reveal that EVs can traverse the zona pellucida, transferring molecular signals that enhance blastocyst formation and support embryo-maternal crosstalk. EVs have emerged as non-invasive biomarkers for embryo quality, with their cargo providing insights into genetic integrity and developmental competence. Advances in isolation and characterization techniques have identified specific microRNA (miRNAs) and transcription factors within EVs, offering potential for use in preimplantation genetic screening (PGS) and sex determination. Moreover, EV-mediated interactions with the maternal environment are critical for successful implantation, as they modulate gene expression and immune responses in endometrial and oviductal cells. Despite these advancements, challenges persist, including the standardization of EV isolation methods and the low yield of EVs DNA from spent culture media. Future research should aim to refine analytical techniques, explore EV-miRNA profiling, and investigate the mechanisms underlying EV-mediated signaling. By addressing these gaps, EVs could revolutionize embryo selection and reproductive technologies, offering new strategies to improve outcomes in assisted reproduction and animal breeding.

Is germline genome-editing person-affecting or identity-affecting, and does it matter?

Writers have debated whether germline genome-editing is person-affecting or identity-affecting. The difference is thought to be ethically relevant to whether we should choose genome-editing or choose preimplantation genetic diagnosis and embryo selection, when seeking to prevent or produce bad conditions (e.g., cystic fibrosis, or deafness) in the individuals who will grow from the embryo edited or selected. We consider the very recent views of three prominent bioethicists and philosophers who have grappled with this issue. We claim that both sides are right, but that the sense in which genome-editing is person-affecting is less important, morally, when the aim is to have healthy children. Since this is the predominant objective of engaging in embryo selection and genome-editing, and since there are certain risks, at least for now, with genome-editing, it remains better, morally, to engage in embryo selection than genome-editing.

Embryoscopy and targeted embryo biopsy for the management of early abortion.

To evaluate the safety, accuracy, and effectiveness of embryoscopy for the management of early abortion and to test the hypothesis that targeted embryo and chorionic villi sampling avoids maternal cell contamination (MCC) for genetic testing of products of conception (POC). This ambispective study included 74 consecutive patients presenting with early abortion. Gestations between 5 and 9weeks, obtained either spontaneously or through assisted reproductive technologies were included. Embryoscopies were performed under transabdominal ultrasound guidance using a 5-mm hysteroscope and forceps and scissors for sampling and resection of the gestational sac. Primary outcomes were the feasibility of the technique, the diagnostic accuracy as measured by absence of maternal cell contamination and the complication rate. The secondary outcome was the comparison between array-comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) in a subgroup of 20 patients. Seventy-four consecutive procedures were performed, with no cases of maternal contamination and no complications. In 60 patients, a follow-up sonohysterography was performed which showed a normal cavity. The remaining 14 patients had a normal transvaginal ultrasound 1month after the embryoscopy. In the subgroup of 20 patients analyzed by both aCGH and NGS, we had one case of MCC with aCGH and none with NGS. Differences were found in the detection of mosaicism and triploidy. Embryoscopy for uterine evacuation minimizes maternal contamination and post-operative complications. Safe and rapid embryoscopy furnishes prompt and reliable genetic analysis of POC that is of great importance in clinical management of early pregnancy failure.

Ultrasound-guided hysteroscopic uterine evacuation in cases of missed abortion.

To describe the hysteroscopic, ultrasound-guided removal of missed abortion products of conception, emphasizing identification and resection of the different layers, visualization of the embryo and yolk sac, and maternal contamination-free direct sampling of the embryo and trophoblast. Illustration of a step-by-step innovative ultrasound-guided surgical technique for uterine evacuation during optically directed embryo and trophoblast biopsy. Private university-affiliated infertility center. Women with missed abortion, with or without a history of infertility or recurrent pregnancy loss. The 7 patients included in this video gave consent for publication of the video and posting of the video online including social media, the journal website, and scientific literature websites. Missed abortion was diagnosed by transvaginal ultrasound confirming loss of fetal heartbeat. After informed consent, the patient was brought to the operating room. Under deep sedation, a 5-mm hysteroscope was inserted transcervically, and the uterine cavity was distended with normal saline (80-100 mm Hg). The implantation site was identified by direct visualization and transabdominal ultrasound. The gestational sac was opened with hysteroscopic scissors, and the extracoelomic cavity was entered. The yolk sac and embryo were visualized and evaluated. Embryo and chorionic villi sampling were performed with hysteroscopic forceps. After removal of the embryo, resection of the gestational sac was accomplished with hysteroscopic forceps and scissors. Step-by-step educational video. Optically identified embryonic and trophoblastic tissue and the corresponding cytogenetic result were obtained in all cases, without maternal cell contamination. There were no intraoperative complications. Patients' follow-up revealed no cases of retained products of conception or intrauterine adhesions. All patients who attempted pregnancy were successful, without complications. Ultrasound-guided hysteroscopic removal of a missed abortion is noninvasive and potentially safer than conventional surgical techniques. It allows comparison of trophoblastic vs. embryo biopsy and resolution of, for example, mosaicism in placental pole preimplantation embryo biopsies. A potential disadvantage is the relative complexity of the procedure compared with routine dilation and curettage (1-5).

Let 'Pregnant Women Choose the Destiny for Themselves and Their Child'. How Fertility Clinic Digital Platforms Frame Preimplantation Genetic Testing (PGT) in Spain.

Preimplantation Genetic Testing (PGT) is used to select in vitro embryos for distinct clinical contexts and purposes. PGT for monogenic conditions (PGT-M), also known as Preimplantation Genetic Diagnosis (PGD), enables the prevention of passing on a known genetic disorder to one's offspring. Conversely, PGT for aneuploidies (PGT-A), or Preimplantation Genetic Screening (PGS), is used to improve IVF success rates in fertility patients and increase confidence about the health outcomes of potential offspring. Using discourse analysis, we examine how Spanish fertility clinic digital platforms frame these techniques and their associated subjectivity processes. We find: first, an excessively unproblematic portrayal of experimental innovations such as PGT; second, a linguistic, semantic and clinical overlap between 'diagnosis' and 'screening', which increases the genetic responsibility of couples or women without known genetic conditions regarding their prospective children; and third, the use of genomics as a modulator of female fertility and as a means to control maternal age-related decline. Ultimately, this discourse positions PGT as a routine IVF component, serving as an assurance tool for both treatment success and the health of the potential baby. This narrative reflects the speculative turn in assisted reproduction, emphasising new forms of responsibility and choice of would-be mothers.

Systematic review and Meta-analysis of the impact of the re-freezing and re- biopsy embryos on reproductive outcomes in patients undergoing freeze-thaw embryo transfer.

During FET cycles in IVF/ICSI patients (including PGT patients), transfer of embryos that have been thawed may be abandoned for medical or personal reasons, resulting in the need to refreeze embryos. Typically, embryos from patients undergoing preimplantation genetic testing (PGT) are cryopreserved after biopsy, pending test results. However, in the absence of a clear result, another biopsy is required and the embryo is frozen again to await the results for future use. To explore whether refreezing and re-biopsy affect reproductive outcomes DATA SOURCES: Computer search was conducted in PubMed, EMBASE, Cochrane Library, Web of Science, CBM, CNKI, WanFang Data, and VIP databases and searched until May, 2023. STATA/MP software was utilized for conducting data analysis. Dichotomous outcome data were pooled to calculate odds ratios (ORs) and their corresponding 95% confidence intervals (CIs). Continuous outcome data were combined using an inverse variance model to determine the mean difference (MD) between the two groups. Random-effects and fixed-effects meta-analysis models were employed to assess heterogeneity. Subgroup analysis was conducted based on different freezing methods and various embryo types. The primary outcome measure was the live birthrate, with secondary indicators including clinical pregnancy rate, implantation rate, miscarriage rate, ectopic pregnancy, preterm delivery, average birth weight of neonates, and neonatal malformation. This study included 19 retrospective studies with a total of 11,024 FET cycles. Across the FET cycles, re-cryopreservation, compared to once-cryopreservation demonstrated reduced live birthrates (OR=0.79; 95% CI: 0.60 to 0.92; I2=21.7%, P=0.000), reduced clinical pregnancy rates (OR=0.74; 95% CI: 0.60 to 0.92, I2=56.9%, P=0.006), and increased miscarriage rates (OR=1.27; 95% CI: 1.03 to 1.55, I2=37.1%, P=0.024). Pregnancy outcomes following re-biopsies, revealing significantly lower live birth rates after re-biopsies compared with single biopsy (OR = 0.65; 95%CI: 0.45 to 0.94, I2=43.5%; P=0.024). Similarly, re-biopsies were associated with reduced clinical pregnancy rates (OR = 0.75; 95%CI: 0.54 to 1.03, I2=29.6%) and increased miscarriage rates (OR= 1.54; 95%CI: 0.89 to 2.66, I2=13.0%) compared to single-biopsy. Re-frozen embryos compared to once-frozen embryos suggests a decrease in live birth rates and clinical pregnancy rates, coupled with an increase in miscarriage rates, with negligible influence on neonatal outcomes. Similarly, re-biopsy yields comparable results, leading to a reduction in live birth rates.

Protecting Future Generations From Hereditary Genetic Disorders Using Preimplantation Genetic Diagnosis: A Narrative Review Article.

Preimplantation genetic diagnosis (PGD) is provided by majority of reproductive clinics in the United States (US), and PGD is used in many in vitro fertilization (IVF) procedures every year. PGD is extensively used to screen for certain genetic abnormalities and aneuploidy in individuals undergoing IVF. Genetic disorders are very prevalent in Saudi Arabia. The high prevalence of consanguinity in the population explains, to a great extent, the incidence of genetic disorders being relatively higher in the Kingdom of Saudi Arabia (KSA) compared to many other countries. Estimates range from 6% to 10% among all live births, and at least one study estimated that up to 30% of the population couldbe affected by a genetic disorder at any time in their lifetime.Therefore, a preventive measure such as PGDis useful for detecting genetic disorders before implantation. In KSA,genetic disorders are prevalent with a high psychological and financial burden. A diagnostic procedure like PGD is useful for detecting genetic disorders. It is used to analyze embryos under the IVF cycle. Then, a biopsy is taken from the embryos and analyzed using techniques such as polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH). Only healthy embryos are transferred to the uterus, thus eliminating the need for a parental diagnostic test that comes with substantial risk to the mother and the fetus. PGD is used for the detection of genetic abnormalities such as sex-linked diseases and chromosomal abnormalities, helping parents with genetic disorders to conceive a healthy child. Some of the limitations of PGD are its unavailability and the high cost, which limitthe access for parents of low socioeconomic status. It creates many decision-making problems for the facilities and parents. Our objectives include giving an overview of PGD history, demonstrating indications for this procedure, explaining its techniques, and discussing the ethical issues surrounding it. PGD offers improved IVF results and reduced genetic disorder prevalence but also has disadvantages like high costs, limited access, and ethical concerns.

Molecular basis of mucopolysaccharidosis type II (Hunter syndrome): first review and classification of published IDS gene variants

PurposeMucopolysaccharidosis type II (MPS II) is a rare X-linked lysosomal storage disorder caused by genetic alterations in the iduronate 2-sulfatase (IDS) gene. A wide range of variants has been reported for different countries and ethnic groups. We collected, analyzed and uniformly summarized all published IDS gene variants reported in literature up to June 2023, here providing the first worldwide review and classification.MethodsData was obtained from a literature search, conducted in PubMed and Google. All data was analyzed to define the most common alleles, geographic distribution and genotype-phenotype correlation. Moreover, point variants were classified according to their pathogenicity, based on the ACMG guidelines.ResultsSeveral types of variants have been described in the IDS gene, including intrachromosomal homologous recombination occurring between the homologous regions of IDS gene and its pseudogene IDSP1. Overall, we collected 2852 individuals from 2798 families, including 24 female patients. Most families carried missense variants, followed by large deletions-insertions and complex rearrangements, small frameshift deletions/insertions and nonsense variants. Based on ACMG guidelines, 62.9% of the 779 point variants were classified as “pathogenic”, 35.4% as “likely pathogenic”, and the remaining 13 variants as having “uncertain significance”.ConclusionData from this study confirmed that MPS II is a genetically very heterogeneous disorder, making genotype-phenotype correlation very challenging and in most cases merely unfeasible. Mutation updates are essential for the correct molecular diagnosis, genetic counseling, prenatal and preimplantation diagnosis, and disease management.

Approximate Bayesian computation supports a high incidence of chromosomal mosaicism in blastocyst-stage human embryos.

Chromosome mis-segregation is common in human meiosis and mitosis, and the resulting aneuploidies are the leading cause of pregnancy loss. Preimplantation genetic testing for aneuploidy (PGT-A) seeks to prioritize chromosomally normal embryos for transfer based on genetic analysis of a biopsy of approximately five trophectoderm cells from blastocyst-stage in vitro fertilized (IVF) embryos. While modern PGT-A platforms classify these biopsies as aneuploid, euploid, or mosaic (possessing a mixture of normal and aneuploid cells), the underlying incidences of aneuploid, euploid, and mosaic embryos and the rates of meiotic and mitotic error that produced them remain largely unknown. To address this knowledge gap, we paired a recent method for embryo simulation with approximate Bayesian computation (ABC) to infer rates of meiotic and mitotic error that best explain published PGT-A data. By simulating from these posterior distributions, we also evaluated the chromosomal status of entire embryos. For a published clinical sample, we estimated a 39-43% probability of meiotic error per meiosis, as well as a 1.0-3.0% probability of mitotic error per mitosis, depending on assumptions about spatial clustering of aneuploid cells within mosaic embryos. In addition, our analyses suggest that less than 1% of blastocysts are fully euploid, and that many embryos possess low-level mosaic clones that are not captured during biopsy. These broad conclusions were relatively insensitive to potential misclassification of mosaic biopsies. Together, our work helps overcome the limitations of embryo biopsies to estimate the fundamental rates of cell division errors that are the main causes of human pregnancy loss.

Direct assessment of hereditary hemochromatosis in preimplantation genetic testing.

Hereditary hemochromatosis (HH) is a common genetic disorder characterized by iron overload, which, if undiagnosed, can lead to severe organ damage. There are 4 types of HH. Type 1 HH, the most common form, is primarily caused by a common variant in Western Europe (p.Cys282Tyr, C282Y, or c.845 G>A). It is generally preventable during invitro fertilization if proper genetic testing is performed before implantation. Here, we demonstrated a direct detection and cost-effective approach using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in preimplantation genetic testing (PGT) settings. We began by validating the assay with genomic deoxyribonucleic acid (DNA) from Coriell cell lines of known HFE C282Y genotypes, followed by testing patients' genomic DNA samples. After establishing the assay on genomic DNA, we extended the assay to whole-genome amplified DNA from embryo biopsies. The subjects include cell line samples and human specimens and human embryo biopsies. Patients and embryos either carried or did not carry the HFE C282Y variant in their genome. No intervention was applied. The readout included the genotype of samples at the HFE C282Y locus and accuracy of PCR-RFLP results. An accuracy of >99% was achieved across 80 cell line samples, 38 patient samples, and 81 embryo biopsies. In this study, we demonstrated the feasibility of using the PCR-RFLP approach to PGT. Specifically, we validated the assay for the HFE C282Y variant, the primary cause of type 1 hemochromatosis. The assay was tested on genomic DNA and DNA resulting from whole-genome amplification, achieving >99% accuracy, sensitivity, precision, and specificity. These results also suggest the possibility for extending the PCR-RFLP approach to cover a broader range of conditions, such as spinal muscular atrophy, to benefit more patients currently ineligible for testing at PGT laboratories.

Genetics in Reproductive Medicine

Thanks to advances in technology, genetic testing is now available to explore the causes of infertility and to assess the risk of a given couple passing on a genetic disorder to their offspring. This allows at-risk couples to make an informed decision when opting for assisted reproduction and allows professionals to offer pre-implantation diagnosis when appropriate. Genetic screening of an infertile couple has thus become standard practice for an appropriate diagnosis, treatment, and prognostic assessment. This review aims to highlight the conditions under which genetic screening plays a role in improving reproductive outcomes for infertile couples.

Novel mutation in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II).

A rare type of autosomal recessive skeletal disorder, known as microcephalic osteodysplastic primordial dwarfism (MOPD) type II, causes a wide range of clinical abnormalities, including skeletal dysplasia, microcephaly, abnormal skin pigmentation, insulin resistance, typical facial features, and severe tooth deformities. Given the diverse manifestations of MOPD disorders and the overlapping clinical characteristics among primordial dwarfism (PD) subtypes, mutation analysis is crucial for accurate diagnosis and confirmation of MOPD II. In this study, whole-exome sequencing (WES) and GAP-PCR were employed to identify relevant genetic variants in three patients suspected of having MOPD.The clinical characteristics of three Iranian patients exhibiting hallmark features of MOPD were assessed. All patients were the offspring of consanguineous marriages and were referred from various provinces of Iran. WES was performed, and the identified variants were prioritized according to the standard filtration criteria. In the next step, Sanger sequencing was conducted to validate the candidate variants identified through WES in patients and their parents. Finally, GAP-PCR was implemented to resolve conflicting results between WES and Sanger sequencing for one of the patients.Analysis of three distinct cases revealed a novel homozygous copy number variation (CNV) in Case 3, consisting of a 490bp deletion harboring exon 19 in the PCNT gene. Additionally, a nonsense homozygous variant in the PCNT gene (c.2812C > T, p.Gln 938*) was found in Cases 1 and 2. This pathogenic variant has been previously documented in the literature.Reporting a novel deletion in the PCNT gene improves genetic testing services, including PND and pre-implantation genetic diagnosis (PGD) for MOPD II.

Camptodactyly-Arthropathy-Coxa Vara-Pericarditis Syndrome Caused by Truncating Mutations in the Prg4 Gene: Case Series and Literature Review

Introduction: Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive condition characterized by early-onset camptodactyly, noninflammatory arthropathy, coxa vara deformity, and, rarely, pericardial effusion. The disease gene has been assigned to human chromosome regions 1q25-q31, and truncating mutations have been identified in the proteoglycan-4 (PRG4) gene formerly known as megakaryocyte stimulating factor gene. Methods: A literature review was performed with the findings in patients in terms of CACP syndrome. Also, whole-exome sequencing was performed for all cases. Segregation analyses of the detected variants were performed according to the possibilities. Results: We present 3 Turkish patients with CACP syndrome mimicking juvenile idiopathic arthritis (JIA). All patients were exposed to biologic therapy due to recalcitrant JIA. We have detected two pathogenic PRG4 variants. Case 3 had a novel pathogenic PRG4 variant not reported for the CACP syndrome so far. These two variants cause premature truncation of the protein. A deletion was detected in case 1 in the homozygous state in the PRG4 gene (NM_005807.6: c.3848del, p.Gly1283GlufsTer6, chr1-186281360-G-). A previously described deletion was detected in case 2 and case 3 in the homozygous state in the PRG4 gene (NM_005807.6: c.1910_1911delCT, p.Pro637ArgfsTer9, chr1-186276761-CT). Conclusion: In the current study, we report three pathogenic PRG4 variants including a novel mutation. We consider that a detailed anamnesis, including kinship and meticulous physical examination of camptodactyly in the absence of inflammatory response, may reveal CACP syndrome masquerading as JIA. The PRG4 gene analysis presents the early diagnosis for patients and prenatal counseling and preimplantation genetic diagnosis for carrier families.

The frontier of precision medicine: application of single-cell multi-omics in preimplantation genetic diagnosis.

The advent of single-cell multi-omics technologies has revolutionized the landscape of preimplantation genetic diagnosis (PGD), offering unprecedented insights into the genetic, transcriptomic, and proteomic profiles of individual cells in early-stage embryos. This breakthrough holds the promise of enhancing the accuracy, efficiency, and scope of PGD, thereby significantly improving outcomes in assisted reproductive technologies (ARTs) and genetic disease prevention. This review provides a comprehensive overview of the importance of PGD in the context of precision medicine and elucidates how single-cell multi-omics technologies have transformed this field. We begin with a brief history of PGD, highlighting its evolution and application in detecting genetic disorders and facilitating ART. Subsequently, we delve into the principles, methodologies, and applications of single-cell genomics, transcriptomics, and proteomics in PGD, emphasizing their role in improving diagnostic precision and efficiency. Furthermore, we review significant recent advances within this domain, including key experimental designs, findings, and their implications for PGD practices. The advantages and limitations of these studies are analyzed to assess their potential impact on the future development of PGD technologies. Looking forward, we discuss the emerging research directions and challenges, focusing on technological advancements, new application areas, and strategies to overcome existing limitations. In conclusion, this review underscores the pivotal role of single-cell multi-omics in PGD, highlighting its potential to drive the progress of precision medicine and personalized treatment strategies, thereby marking a new era in reproductive genetics and healthcare.

Pregnancy and inherited aortopathies: insights from specialized care

Abstract Background Genetic counselling, pregnancy follow-up and delivery planning in women with aortopathy should be conducted by a multidisciplinary team in an expert centre. Purpose Our objective was to analyze the impact of pregnancy on aortopathy outcomes in a centre specialized in inherited cardiovascular conditions in the United Kingdom. Methods All women with aortopathy referred to our centre due to pregnancy between 2016 and 2023 were retrospectively analyzed. Demographic, clinical, obstetric, genetic, electrocardiographic, and multimodal imaging variables were collected. Results Between 2016 and 2023, 22 women with aortopathy were referred to our centre for pregnancy follow-up and delivery planning. Among them, 14 (63.6%) had Marfan syndrome (FBN1+), 4 (18.2%) family history of aortic dissection without known genetic mutations, 2 (9.1%) bicuspid aortic valve with aortic dilation and 2 (9.1%) Loeys-Dietz syndrome (SMAD3+). The average number of births per patient was 1.55. Among those with an identified mutation, 4 (25%) underwent preimplantation diagnosis. In total, there were 40 pregnancies resulting in 34 live births. 15 women (68.2%) had an aortic root dimension <40mm and 7 (31.8%) ≥40mm. There were 4 (26.7%) and 5 (71.4%) patients in each group under beta-blockers. Out of the total 40 pregnancies, there were 6 (15%) miscarriages, all in the first trimester, 2 (5%) cases of preeclampsia and 1 (2.5%) case of gestational diabetes. There were no statistically significant differences between these complications and the aortic root dimension (8 (20%) <40mm vs 1 (2.5%) ≥40mm; p = 0.160) or the absence or presence of treatment (3 (7.5%) vs 6 (15%); p = 0.769). Regarding delivery, 16 patients (72.7%) underwent vaginal delivery and 6 (27.3%) has a caesarean section. After delivery, there were 6 cases of major bleeding, 4 (10%) after vaginal delivery and 2 (5%) after caesarean (p=0.376). One patient had a subacute type A aortic dissection in the context of Marfan syndrome with an aortic root of 40mm before pregnancy. No significant differences were observed in the occurrence of these complications based on the aortic root dimension (5 (12.5%) <40mm vs 2 (5%) ≥40mm; p = 0.928) or the absence or presence of treatment (2 (5%) vs 5 (12.5%) respectively; p = 0.591). 100% of the patients survived pregnancy and the postpartum period. Conclusions Our findings underscore the complexity of managing aortopathy during pregnancy. This highlights the importance of a comprehensive risk assessment for precise pregnancy and delivery planning.

Steady morphokinetic progression is an independent predictor of live birth: a descriptive reference for euploid embryos.

Can modelling the longitudinal morphokinetic pattern of euploid embryos during time-lapse monitoring (TLM) be helpful for selecting embryos with the highest live birth potential? Longitudinal reference ranges of morphokinetic development of euploid embryos have been identified, and embryos with steadier progression during TLM are associated with higher chances of live birth. TLM imaging is increasingly adopted by fertility clinics as an attempt to improve the ability of selecting embryos with the highest potential for implantation. Many markers of embryonic morphokinetics have been incorporated into decision algorithms for embryo (de)selection. However, longitudinal changes during this temporal process, and the impact of such changes on embryonic competence remain unknown. Aiming to model the reference ranges of morphokinetic development of euploid embryos and using it as a single longitudinal trajectory might provide an additive value to the blastocyst morphological grade in identifying highly competent embryos. This observational, retrospective cohort study was performed in a single IVF clinic between October 2017 and June 2021 and included only autologous single euploid frozen embryo transfers (seFET). Reference ranges were developed from [hours post-insemination (hpi)] of the standard morphokinetic parameters of euploid embryos assessed as tPB2, tPNa, tPNf, t2-t9, tSC, tM, tSB, and tB. Variance in morphokinetic patterns was measured and reported as morphokinetic variance score (MVS). Nuclear errors (micronucleation, binucleation, and multinucleation) were annotated when present in at least one blastomere at the two- or four-cell stages. The blastocyst grade of expansion, trophectoderm (TE), and inner cell mass (ICM) were assessed immediately before biopsy using Gardner's criteria. Pre-implantation genetic diagnosis for aneuploidy (PGT-A) was performed by next-generation sequencing. All euploid embryos were singly transferred in a frozen transferred cycle and outcomes were assessed as live birth, pregnancy loss, or not pregnant. Association of MVS with live birth was investigated with regression analyses. TLM data from 340 seFET blastocysts were included in the study, of which 189 (55.6%) resulted in a live birth. The median time for euploid embryos to reach blastulation was 109.9 hpi (95% CI: 98.8-121.0 hpi). The MVS was calculated from the variance in time taken for the embryo to reach all morphokinetic points and reflects the total morphokinetic variability it exhibits during its development. Embryos with more erratic kinetics, i.e. higher morphokinetic variance, had higher rates of pregnancy loss (P = 0.004) and no pregnancy (P < 0.001) compared to embryos with steadier morphokinetic patterns. In the multivariable analysis adjusting for ICM, TE grade, presence of nuclear errors, and time of blastulation, MVS was independently associated with live birth (odds ratio [OR]: 0.62, 95% CI: 0.46-0.84, P = 0.002) along with ICM quality. Live birth rate of embryos with the same ICM grading but different morphokinetic variance patterns differed significantly. Live birth rates of embryos exhibiting low MVS with ICM grades A, B, and C were 85%, 76%, and 67%, respectively. However, ICM grades A, B, and C embryos with high MVS had live birth rates of 65%, 48%, and 21% (P < 0.001). The addition of the MVS to embryo morphology score (ICM and TE grading) significantly improved the model's AUC value (0.67 vs 0.62, P = 0.015) and this finding persisted through repeat cross-validation (0.64 ± 0.08 vs 0.60 ± 0.07, P < 0.001). The exclusion of IVF cases limits, for now, the utility of the model to only ICSI-derived embryos. The utility of these reference ranges and the association of MVS with various clinical outcomes should be further investigated. We have developed reference ranges for morphokinetic development of euploid embryos and a marker for measuring total morphokinetic variability exhibited by developed blastocysts. Longitudinal assessment of embryonic morphokinetics rather than static time points may provide more insight about which embryos have higher live birth potential. The developed reference ranges and MVS show an association with live birth that is independent of known morphological factors and could emerge as a valuable tool in prioritizing embryos for transfer. This study received no external funding. The authors declare no conflicting interests. N/A.

THE USE OF PREIMPLANTATION DIAGNOSIS IN THE GENERATION OF SAVIOR SIBLINGS: A multidisciplinary study

Preimplantation Genetic Diagnosis (PGD) is a technique used in IVF to analyze embryos and check for the presence of genetic diseases, allowing the selection of healthy embryos. The medicine baby is a child generated for the purpose of treating a sick sibling, being a relevant practice in the medical field because it enables the cure of certain pathologies through the donation of tissues such as blood and bone marrow. The importance of PGD is highlighted, as it allows diagnosing and selecting embryos without genetic diseases, although it is necessary to consider ethical limits to preserve the integrity and dignity of the future child. The objective of this study was to analyze the criteria used in the Preimplantation Genetic Diagnosis for the generation of a drug baby. An exploratory literature review was carried out in databases such as Pubmed, Virtual Health Library, Google Scholar and journals between the years 2012 and 2023, in addition, the film "A proof of love" was analyzed to complement the investigation. While PDG and the drug baby generation advance healthcare in revolutionary ways, it is important to address ethical and social issues comprehensively and sensitively by ensuring that scientific advances are used responsibly and for the benefit of all involved.