Igenomix

This study aimed to investigate potential improvements when implementing endometrial receptivity analysis (ERA)-guided personalized embryo transfer (pET) using euploid blastocyst in patients with one or more previous failed embryo transfers. A total of 270 patients with one or more previous failed embryo transfers were enrolled between 2017 and 2021 in this multicenter retrospective study. These patients were divided into two groups: study cases (ERA-guided pET) (n = 200) or controls (standard embryo transfer) (n = 70). Clinical outcomes compared were pregnancy rate (PR), implantation rate (IR), ongoing pregnancy rate (OPR), and live birth rate (LBR). Clinical results in terms of PR, OPR, and LBR were significantly higher when performing ERA-guided pET (PR: 65.0%; OPR: 49.0%; LBR: 48.2%) compared to standard embryo transfer (PR: 37.1%; OPR: 27.1%; LBR: 26.1%) (P < 0.01). Logistic regression was applied to examine the correlation between ERA and the primary outcome measured, OPR, including demographic variables as covariates. The effect of ERA was significantly associated with OPR (P = 0.002; aOR 2.8, 95% CI 1.5–5.5); furthermore, OPR decreased significantly when body mass index (BMI) values increased (P = 0.04; aOR 0.9, 95% CI 0.8–0.98). These findings support the potential of ERA-guided pET to improve clinical outcomes and address the challenges encountered by patients with previous implantation failures.

Fertility is a dynamic, multifactorial process governed by hormonal, immune, metabolic, and environmental factors. Recent evidence highlights the gut microbiota as a key systemic regulator of reproductive health, with notable impacts on endometrial function, implantation, pregnancy maintenance, and the timing of birth. This review examines the gut-endometrial axis, focusing on how gut microbial communities influence reproductive biology through molecular signaling pathways. We discuss the modulatory roles of microbial-derived metabolites-including short-chain fatty acids, bile acids, and tryptophan catabolites-in shaping immune tolerance, estrogen metabolism, and epithelial integrity at the uterine interface. Emphasis is placed on shared mechanisms such as β-glucuronidase-mediated estrogen recycling, Toll-like receptor (TLR)-driven inflammation, Th17/Treg cell imbalance, and microbial translocation, which collectively implicate dysbiosis in the etiology of gynecological disorders including endometriosis, polycystic ovary syndrome (PCOS), recurrent implantation failure (RIF), preeclampsia (PE), and preterm birth (PTB). Although most current evidence remains correlational, emerging insights from metagenomic and metabolomic profiling, along with microbiota-depletion models and Mendelian randomization studies, underscore the biological significance of gut-reproductive crosstalk. By integrating concepts from microbiology, immunology, and reproductive molecular biology, this review offers a systems-level perspective on host-microbiota interactions in female fertility.

BORCS5 encodes a subunit of the BLOC-one-related complex (BORC), which is known to mediate the kinesin-dependent anterograde movement of lysosomes. Using whole-exome sequencing, we identified 12 cases from seven families carrying bi-allelic BORCS5 variants, including four loss-of-function and two missense variants. Carriers of homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction. Our study reveals a novel role for BORCS5 in the regulation of lysosomal function, in addition to its known role in the anterograde movement of lysosomes, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.

Studying phenotype-specific regulatory mechanisms is crucial to understanding the molecular basis of diseases and other complex traits. However, existing approaches for constructing multi-omic regulatory networks MO-RN are scarce, and most cannot integrate diverse omics modalities, incorporate prior biological knowledge, or infer phenotype-specific networks. To address these challenges, we present MORE (Multi-Omics REgulation), a novel R package for inferring multi-modal regulatory networks. MORE is available at https://github.com/BiostatOmics/MORE and supports any number and type of omics layers while optionally incorporating prior regulatory knowledge. Leveraging advanced regression-based models and variable selection techniques, MORE identifies significant regulatory relationships. This tool also provides useful functionalities for the biological interpretation of MO-RN: network visualisations, differential regulatory networks, and functional enrichment analyses of key network features. We evaluated MORE on simulated multi-omic datasets and benchmarked it against state-of-the-art tools. Our tool consistently outperformed other methods regarding accuracy in identifying significant regulators, model goodness-of-fit, and computational efficiency. We further applied MORE to a multi-omic ovarian cancer dataset to uncover tumour subtype-specific regulatory mechanisms associated with distinct survival outcomes. This analysis revealed differential regulatory patterns to understand the molecular basis of each subtype. By addressing the limitations of methods for multi-omic network inference, MORE represents a valuable resource for studying regulatory systems. Its ability to construct phenotype-specific regulatory networks with high accuracy and interpretability positions it as a useful resource for researchers seeking to unravel the complexities of molecular interactions and regulatory mechanisms across diverse biological contexts.

Copy number variants (CNVs) contribute significantly to the pathogenicity of rare genetic diseases and tend to have a more severe effect on phenotype compared to single nucleotide variants (SNVs). In the past decades, exome sequencing (ES) has proven valuable input in the characterization of underlying genetic defects. Our aim was to investigate the impact of integrating CNV analysis tools into standard ES analysis on its diagnostic yield. We worked on ES data from an original cohort of 840 patients, in whom the first analysis was able to detect causative SNVs and indels in 383 (45.6%). Using the ExomeDepth algorithm, clinically relevant CNVs were identified in 55 patients out of the 457 unsolved cases, thus enhancing the diagnostic yield to 52.1%. Among the enrolled subjects, neurodevelopmental delay was the most prevalent phenotype. The detected CNVs comprised 43 deletions (74.1%) and 15 duplications (25.9%), ranging in size from 94 bp to 94.3 Mb, and were classified as 56 pathogenic/likely pathogenic and 2 uncertain with high interest. The study presents further evidence that incorporating CNV analysis tools into ES pipelines improves the diagnostic yield and emphasizes the involvement of CNVs in the etiology of genetic disorders.

To study the influence of parental age on aneuploidy rates (AR) in PGT-A cycles and on the recurrence rate. A total of 16,029 PGT-A cycles were studied over a 9-year period. The median age was 40.0 [37.0; 41.0] in women and 40.0 [37.0; 43.0] in men. In 48.3%, the biopsy was performed on day 3 embryos (D3E) and in 51.7% on blastocysts (79.5% using NGS). In women, the AR was almost constant at < 50% until the age of 35 but increased steadily to reach > 90% at 44. The AR pattern varied according to embryo stage and was considerably higher in D3E, with a steeper curve. A U-pattern was observed in D3E, whereas this was not seen in blastocysts. In the blastocysts analyzed using NGS, trisomy 21 increased sixfold (from < 1% at < 30 to nearly 5% in women aged 40), whereas trisomies 13 and 18 increased their frequency twofold. After 3 biopsied blastocysts studied using NGS, 100% of women aged ≤ 30 had at least 1 euploid embryo, vs 96% aged 31-35, almost 80% aged 36-40, 50% aged 41-45, and 33% aged 46-50. In terms of the man's age, the non-adjusted analysis revealed a correlation with AR. However, after correcting for the woman's age, no correlation was observed. The man's age was not associated with any of the aneuploidies potentially resulting in a newborn. Carrying out PGT-A systematically in IVF cycles from the age of 38-39 is highly recommended. Advanced paternal age does not carry an increased risk of aneuploidy for the embryo and does not in itself constitute an indication for PGT-A.

Ensemble ocean model experiments can be useful to understand the extent to which internal variability has exerted an influence on a given observation, or indeed modelled event. This is important in contexts such as that of ongoing climate change, for example, where this probabilistic information can be useful for the purposes of detection and attribution. However, ensemble simulation has certain disadvantages, including its very high computational and energetic cost, the technical skill required to implement such modelling strategies, and the inherent dependence of the results on model physics. The aim of this study is to address these drawbacks by directly estimating the ensemble mean using statistical methods applied to individual model simulations, or observations. The effects of internal variability should be strongly reduced in these artificial ensemble mean estimates, enabling better insight into the direct effects of atmospheric forcing on the chosen ocean variables.In previous work, we showed that the ensemble mean sea surface height can be estimated with good accuracy by filtering an individual member of the ensemble. Here, we extend this result to sea surface temperature (SST), which requires a more complicated spatiotemporal filter to estimate the ensemble mean, but again shows good agreement with the true ensemble mean SST at very low computational cost. However, examination of the full 3D temperature fields show a more complicated spectral coherence signature, suggesting that application of the filtering method to these 3D fields would be more challenging. In a second step, a neural network is thus trained to reproduce 3D ocean temperature fields using SST and sea surface height as inputs. By combining the filtered fields with the neural network, first estimates are made of the ensemble mean 3D temperature field, based on observations. Comparisons with the true ensemble mean 3D fields are encouraging, and suggest that the method may be useful as a cheap alternative to numerical simulation to better identify the atmospheric influence on ocean variability.

The hyperandrogenic non-classic congenital adrenal hyperplasia (NCAH) is an autosomal recessive disorder thatcan lead to a decrease in reproductive function in women due to alterations in hormone levels. Couples in which thewoman is affected must investigate the occurrence of the mutation in the partner to assess the possibility of passing onthe condition on their offspring. In such cases, genetic counseling plays a crucial role in educating the patient aboutthe risk of having a child with the same disorder. Additionally, assisted reproduction techniques (ART), includingpreimplantation genetic testing for monogenic diseases (PGT-M), are important to increase the chances of the coupleconceiving a healthy child. In this case report, we describe a multidisciplinary approach aimed at achieving two infantswho appeared unaffected by the classic form of the condition. The couple carried variants in CYP21A2 gene, andthe woman, affected by NCAH, presented a novel variant.

Abstract Study question Is embryonic aneuploidy, as determined by Next Generation Sequencing (NGS) based Pre-Implantation Genetic Testing for Aneuploidy (PGT-A) related to female ethnicity? Summary answer In this study, when determining aneuploidy through NGS-based PGT-A, female ethnicity did not have an impact on embryonic aneuploidy. What is known already Inequalities in pregnancy outcomes following in-vitro fertilization (IVF) have often been attributed to potential disparities in genetic susceptibility, with past studies showing higher pregnancy rates in older Caucasian patients compared to younger South-Asian patients. With aneuploidy as one of the best-characterized barriers to IVF success, critics argue that potential ethnic variations in aneuploidy rates may contribute to inequalities in IVF success, raising concerns about the appropriateness of standardized protocols. Proponents stress the importance of personalized medicine accounting for individual genetic backgrounds. Acknowledging genetic diversity and ensuring equitable access to successful fertility treatments remains a complex challenge. Study design, size, duration In this retrospective cohort review, data reflecting 4,354 women undergoing an IVF±ICSI cycle with concomitant NGS-based PGT-A from 65 centres in the United Kingdom, India and Japan was requested. Trophectoderm biopsy results from 16,513 embryos tested through a single genetic laboratory over a five-year period (2019-2023) were analysed. Patients were categorised by ethnicity (Caucasian, African, East Asian, or South Asian) and further stratified by age (&amp;lt;35, 35-37, 38-39, 40-42, &amp;gt;42). Participants/materials, setting, methods Women aged between 25–45 years undergoing an IVF±ICSI cycle with concomitant NGS-based PGT-A were included. Patients undergoing PGT for inherited genetic disorders (PGT-M) or gamete donation cycles were excluded, and only autologous oocyte cases were included. Trophectoderm biopsy was performed on day 5, 6 or 7 and NGS was performed from amplified deoxyribonucleic acid (DNA). Primary outcome of interest was aneuploidy rate (&amp;gt;30% abnormality). Statistical analysis included ANOVA, Kruskal Wallis, and linear regression tests analysis. Main results and the role of chance In our analysis, the mean number of embryos tested overall was 3.46 (SD 2.07) and the mode was 4. The mean number was 3.84 for South Asian, 3.47 for Caucasian, 2.4 for African and 2.87 for East Asian. This was not statistically different between groups (P = 0.48). Subgroup analysis did not identify any statistically significant differences in the number of oocytes retrieved, MII oocytes retrieved and fertilization rates. When categorising by female age alone, there was a statistically significant difference in aneuploidy and female age overall (&amp;lt;35: 32.1±29.7%; 35-37: 42.1±31.3%; 37-39: 50.4±29.3%;40-42: 64.7±33.5% and &amp;gt; 42:73.9±38.7%, p-value: &amp;lt;0.001). When subcategorised by ethnicity, linear regression analysis did not identify a significant association with aneuploidy rate and ethnicity. The was no statistically significant difference in mean aneuploidy rate by ethnicity: East Asian 67.2±32.2%, African 58.3±42.2%, European 55.6±35.6%, and South Asian 53±32.4% (p-value 0.57). With Caucasian as the reference population, coefficients for South Asian (3.20, p-value:0.61), East Asian (8.50 p-value: 0.31), and African (7.20, p-value: 0.60) were not statistically significant. No statistically significant differences in aneuploidy rates were observed across female age categories (&amp;lt;35, 35-37, 38-39, 40-42, &amp;gt;42) and ethnicities, with a p-value of 0.17. Limitations, reasons for caution The study type was retrospective in nature. Ethnic groups are not homogenous, and there can be significant genetic, cultural, and environmental diversity within a group. Failure to account for this heterogeneity may result in oversimplification and misinterpretation of findings. There was under representation of patients from African origin (2%). Wider implications of the findings These data do not support differences in embryonic aneuploidy among various ethnicities in patients undergoing IVF±ICSI /NGS-PGT-A. We limited our analysis to a single genetic laboratory to reduce reporting variation and technical confounders. It does not appear that specific recommendations for aneuploidy screening should be made based upon ethnic heritage. Trial registration number Not applicable