Journal of Assisted Reproduction and Genetics最新文献

Purpose: To investigate whether the levels of mTOR signaling and ribosome biogenesis proteins in cumulus cells (CCs) can serve as non-invasive biomarkers for predicting embryo quality and pregnancy outcomes in women undergoing IVF.

Methods: In this prospective study, discarded CCs were collected from 83 IVF patients. The protein levels of mTOR, phosphorylated mTOR (p-mTOR), ribosomal protein S6 (RPS6), and phosphorylated S6 (p-RPS6) were quantified by Western blot and normalized to β-actin. These molecular data were correlated with clinical parameters, including ovarian reserve, embryonic development, and pregnancy outcomes. Statistical analyses were performed to determine optimal predictive thresholds and to evaluate single and combined protein models.

Results: Reduced levels of p-mTOR, p-RPS6, and RPS6 in CCs were robustly associated with superior IVF outcomes. Specific cutoff values were identified (e.g., p-mTOR < 0.45, p-RPS6 < 0.80) for predicting enhanced blastocyst formation and higher clinical pregnancy rates. Combining these biomarkers into multi-protein models significantly improved predictive accuracy for both embryonic development and pregnancy success compared to any single protein alone.

Conclusion: The assessment of p-mTOR, p-RPS6, and RPS6 in cumulus cells provides a powerful, non-invasive strategy for prognostic assessment in IVF. A molecular profile characterized by lower levels of these proteins is indicative of high oocyte developmental competence and a greater likelihood of successful pregnancy, offering a valuable tool for clinical decision-making prior to embryo transfer.

Purpose: To compare live birth rates (LBRs) between mosaic and euploid embryos.

Methods: Retrospective cohort study analyzing frozen mosaic (56) and euploid (819) embryos tested with next generation sequencing, transferred between October 2018 and December 2023. The primary outcome was LBR per embryo transferred. Secondary outcomes included LBR per embryo transfer cycle, implantation rate (IR), miscarriage rate (MR), double embryo transfer (DET) rate, twin rate, high-level (HL) versus low-level (LL) mosaicism, segmental or whole chromosomal mosaicism, freeze day and grade, and neonatal outcomes. Chi-squared and student t-test were applied, with significance set at p < 0.01.

Results: Per embryo, mosaic and euploid embryos had similar LBR (50.0% versus 51.8%, p = 0.80) and IR (55% versus 56%, p = 0.88). Per cycle, biochemical pregnancy (22.0% versus 17.8%, p = 0.41), clinical pregnancy rate (53.1% versus 56.2%, p = 0.77), and MR (7.7% versus 7.6%, p = 1.00) were not significantly different. LBR in LL versus HL mosaics was 59.4% versus 37.5% (p = 0.18) and 48% versus 50% for segmental versus whole chromosomal defects (p = 1.00). Mosaic embryos were transferred in significantly older patients (37.5 vs 36.1 years, p = 0.01), but age did not affect LBR after adjustment at the time of embryo transfer (p = 0.65). DET was more frequent with mosaic than euploid embryos (41% versus 4.8%, p < 0.001), yielding a higher twin LBR (21% versus 2.7%, p < 0.001).

Conclusion: Mosaic embryos had nearly identical LBR and MR to euploid embryos, supporting transfer before repeating IVF retrieval. Given the elevated twin risk with mosaic DET, single embryo transfer should be prioritized for all tested embryos.

Purpose: Aneuploidy is the most common genetic abnormality in human embryos and is one of the leading causes of embryo transfer failure. We aimed to identify candidate genes linked to mitotic-origin aneuploidy.

Methods: A control group of 588 euploid embryos and a case group of 236 mosaic embryos were utilized. Sequence alignment was first conducted to identify single nucleotide polymorphism (SNP) loci. Quality control (QC) and principal component analysis (PCA) were then performed to filter the SNPs and samples. The association test was carried out to identify significant variants. Fine mapping and gene sorting were used to screen and sort the candidate genes.

Results: Following variant identification, 10,650,011 SNPs were detected in 824 enrolled embryos. After quality control (QC), principal component analysis (PCA), and imputation, 496,728 SNPs across 762 embryos (226 cases and 536 controls) were retained. Association analysis identified 70 SNPs reaching genome-wide significance (p < 5e^-8). Following annotation, 37 variants within 27 genes were considered functional. Gene Ontology (GO) analysis revealed enrichment in innate immune and protein homeostasis pathways. Fine mapping and gene prioritization highlighted EMP2 as a candidate gene of mitotic error. We found that EMP2 may play a critical role in cell-cycle control and endometrial receptivity.

Conclusion: In this study, we performed genome-wide association analysis on embryonic sequencing data and identified EMP2 on chromosome 16 as a potential gene implicated in mitotic-origin aneuploidy. Further verification experiments are required to confirm the functions of candidate genes during embryogenesis.

Objective: To evaluate follicular fluid (FF) SCUBE1 levels as a novel angiogenesis-associated biomarker and investigate its role in reflecting the follicular vascular microenvironment and predicting ovarian response in women undergoing assisted reproductive technology (ART).

Methods: This prospective pilot study included 63 women undergoing IVF/ICSI. Paired serum and FF samples were analyzed. Patients were stratified into Poor (< 4 oocytes), Normal (4-10), and High (> 10) responders. SCUBE1 levels were measured via ELISA. The study primarily investigated the relationship between intrafollicular SCUBE1 and the magnitude of ovarian response as an indicator of the follicular "angiogenic switch."

Results: Serum SCUBE1 levels decreased significantly during ovarian stimulation (p < 0.001). However, FF SCUBE1 levels were approximately twofold higher in High Responders compared to Poor Responders (174.04 ± 112.45 vs. 84.66 ± 73.15 ng/mL, p = 0.043). A significant upward trend was confirmed across responder categories (Jonckheere-Terpstra, p = 0.032). In ROC analysis, FF SCUBE1 demonstrated promising predictive value for high ovarian response (AUC = 0.718, 95% CI: 0.532-0.904, p = 0.048). Notably, a cut-off of 59.13 ng/mL yielded a clinically useful 100% Negative Predictive Value (NPV). SCUBE1 levels did not correlate with oocyte maturation, fertilization, or clinical pregnancy.

Conclusion: Follicular fluid SCUBE1 is a dynamic marker of the follicular vascular microenvironment rather than a direct indicator of oocyte genetic competence. Elevated levels in high responders reflect the intensified angiogenic support required for multiple follicle development. Low FF SCUBE1 may serve as a clinical "red flag" for compromised follicular vascularization in cases of unexpected poor response.

Purpose: Infertility affects 1 in 6 couples, yet male fertility assessments often rely on semen analysis alone, which has limited predictive value for treatment success. This study evaluates an epigenetic tool for assessing sperm quality, aiming to provide a more comprehensive view of male fertility and improve personalized treatment strategies.

Methods: De-identified pregnancy outcomes from 537 couples treated at 10 US fertility clinics were analyzed. Partner ages, total motile sperm count, treatment type, and sperm epigenetic quality were considered to assess associations with fertility treatment outcomes.

Results: Men with abnormal sperm epigenetic profiles had significantly lower pregnancy success rates with intrauterine insemination (IUI) compared to those with normal profiles, despite similar sperm motility and concentration. In contrast, pregnancy rates did not differ between abnormal and normal profiles among couples undergoing in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI), suggesting that ICSI may overcome sperm epigenetic quality issues.

Conclusion: This real-world analysis was limited by the availability of detailed clinical and phenotypic data, which may introduce potential confounders. Nevertheless, the findings highlight the clinical value of epigenetic sperm assessment as part of male fertility evaluation and support its potential to guide more effective, personalized fertility treatment pathways.

Purpose: Recurrent pregnancy loss (RPL) is frequently associated with embryonic aneuploidy, yet paternal genetic contributors remain poorly understood. In this study, we investigated the genetic cause of a couple with oligoasthenoteratozoospermia (OAT) and a history of RPL involving recurrent sex chromosome aneuploidies.

Methods: Evaluation included preimplantation genetic testing for aneuploidy (PGT-A) with parental origin analysis, semen analysis, and sperm fluorescence in situ hybridization (FISH). Whole-exome sequencing (WES) was performed to identify pathogenic variants, which were subsequently validated by Sanger sequencing.

Results: WES revealed a homozygous C12orf40 frameshift variant (c.232_233insTT) in the proband and his affected brother. Both brothers exhibited markedly elevated sperm sex chromosome error rates (proband nullisomy:18.8%; brother disomy:10.3%). Across three PGT-A cycles, only 41.7% (5/12) of the blastocysts were euploid, and 85.7% (6/7) of the aneuploid embryos involved sex chromosome abnormalities. Parental origin analysis indicated 72.7% of abnormalities were paternal in origin.

Conclusion: This study identified a previously unreported phenotype of the C12orf40 c.232_233insTT variant, expanding its spectrum from complete meiotic arrest to incomplete arrest with severe meiotic errors and residual spermatogenesis. It provides the first evidence linking this variant to severe OAT and RPL, highlighting a crucial paternal genetic contributor to reproductive failure.

Purpose: Observational studies suggest that children conceived via in vitro fertilization and embryo transfer (IVF-ET) may exhibit altered growth patterns compared to spontaneously conceived children. This study aimed to compare early physical development among children from different modes of conception and to evaluate the specific effects of frozen versus fresh embryo transfer.

Methods: Data from 5,821 children born between 2010 and 2021 were obtained from the Jiangsu Maternal and Child Health Platform, including 2,958 spontaneous conceptions (SC), 2,148 frozen embryo transfers (FET), and 715 fresh embryo transfers (fresh ET). Anthropometric development was assessed from birth to 5 years of age using longitudinal linear mixed-effects models, stratified by singleton and twin pregnancies. Birth outcomes were analyzed secondarily.

Results: Compared to SC among singletons, FET was associated with higher weight (mean difference [MD] 0.14 kg, 95% CI 0.07-0.20), weight gain velocity (MD 0.01 kg/month), BMI z-score, and weight-for-height z-score (WHZ). Fresh ET increased weight and height gain velocities (MD 0.007 kg/month and 0.02 m/month, respectively) without affecting final weight, BMI z-score, or WHZ. Among twins, FET significantly increased weight (MD 0.68 kg, 95% CI 0.28-1.08), weight gain velocity, BMI z-score, and WHZ, while fresh ET only elevated weight gain velocity and BMI z-score. Neither transfer type influenced height gain in twins.

Conclusions: This study identified distinct early childhood growth patterns, with FET associated with increased weight gain and higher BMI/WHZ scores compared to spontaneous conception. These findings underscore the value of growth monitoring in children conceived by assisted reproductive technology.

Purpose: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is an autosomal recessive genetic and multisystem disorder characterized by extensive intracranial calcifications, leukoencephalopathy, and retinal vascular abnormalities, which is primarily caused by mutations in the CTC1 gene. Preimplantation genetic testing (PGT) is a procedure that helps patients choose embryos free of chromosome abnormalities and monogenic diseases for uterine transfer, preventing serious genetic disorders from being passed on to future generations. Here we introduce a family with fetal malformations due to CRMCC. We aimed to identify the pathogenic variants in a family with fetal malformations due to CRMCC and to utilize PGT to prevent the transmission of this genetic disorder to the next generation.

Methods: Whole-exome sequencing (WES) performed on the aborted fetus suggested a novel homozygous mutation in CTC1, and Sanger sequencing revealed that this mutation is inherited from the parents.

Results: The couple decided to undergo PGT for monogenic disorders to avoid disease transmission and achieve a healthy birth. Blastocyst trophectoderm biopsy was performed for whole-genome amplification and next-generation sequencing (NGS)-based PGT to select unaffected embryos, which resulted in the birth of healthy babies.

Conclusion: This is a novel mutation of CTC1 causing CRMCC and also the first PGT case for CRMCC, which expanded the spectrum of CTC1 mutations and will provide a solution for patients to bear healthy offspring using PGT. Furthermore, our study reconfirms the importance of genetic tests in aborted fetuses and genetic counseling.