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Objective: To compare aneuploidy rates among in vitro fertilization (IVF) cycles using preimplantation genetic testing for monogenic disorders (PGT-M) and aneuploidy (PGT-A) compared with IVF cycles using PGT-A alone, and to determine the likelihood of obtaining at least one usable embryo in cycles using PGT-M+PGT-A compared with cycles using PGT-A alone., Design: Retrospective cohort study., Setting: Single genetics laboratory., Patient(s): All IVF cycles for patients aged 18-45 undergoing PGT-A with or without concurrent PGT-M at a single genetics laboratory from November 2019 to March 2023., Intervention(s): Use of PGT-M+PGT-A vs. use of PGT-A alone., Main Outcome Measure(s): Per cycle aneuploidy rate stratified by age, and per cycle likelihood of obtaining at least one usable embryo stratified by age and inheritance pattern of monogenic disease., Result(s): A total of 72,522 IVF cycles were included; 4,255 cycles (5.9%) using PGT-M+PGT-A and 68,267 cycles (94.1%) using PGT-A alone. The PGT-M+PGT-A group was younger than the PGT-A alone group (<35 years old: 56.1% vs. 30.5%). The majority of PGT-M cycles were performed for autosomal dominant pathogenic variants (42.4%), followed by autosomal recessive (36.5%), X-linked dominant (13.3%), and X-linked recessive (7.5%). The median number of embryos biopsied was higher in PGT-A alone compared with PGT-M+PGT-A cycles for patients aged <35, but it was equivalent in all other age groups. Age stratified aneuploidy rates did not significantly differ between PGT-M+PGT-A compared with PGT-A alone cycles. The probability of having a usable embryo declined with increasing age across all inheritance patterns. Compared with PGT-A alone, PGT-M+PGT-A cycles for patients aged ≤40 across all inheritance patterns were significantly less likely to yield a usable embryo, except in cycles for autosomal recessive diseases in the 38-40 age group and X-linked recessive diseases in the 35-37 age group. There were no consistent differences seen between groups in patients over 40. Cycles for patients with autosomal dominant diseases had the lowest likelihood of yielding a usable embryo for patients aged <43., Conclusion(s): In vitro fertilization cycles using PGT-M+PGT-A have similar age-specific aneuploidy rates to those using PGT-A alone. Cycles for patients ≤40 using PGT-M+PGT-A are significantly less likely to yield a usable embryo compared with those using PGT-A alone., Competing Interests: Declaration of Interests R.A.M. has nothing to disclose. M.B.L. has nothing to disclose. A.S. reports employment at Cooper Genomics. M.S. has nothing to disclose. L.K. has nothing to disclose. J.M. reports employment at Cooper Genomics, CooperSurgical preimplantation genetic testing laboratory; data for analysis provided by preimplantation genetic testing laboratory; honoraria from Yosan University, New England Fertility Society; and Eastern Virginia Medical School Embryology Graduate Program; Genetic Counseling Professional Group, Board member 2020-Present, Chair 2022–2023. C.L. reports employment at Cooper Genomics. R.A.R. has nothing to disclose. A.A. has nothing to disclose. L.K. is a board member of Pacific Coast Reproductive Society and Rooting for Robert., (Copyright © 2024 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease characterized by the development of renal cysts and progression to renal failure. Preimplantation genetic testing-monogenic disease (PGT-M) is an alternative option to obtain healthy babies. However, de novo PKD1 mutation of one of the spouses or the absence of a positive family history poses a serious challenge to PGT-M. Here, we described a comprehensive strategy which includes preimplantation genetic testing for aneuploidies (PGT-A) study and monogenic diagnosis study for ADPKD patients bearing de novo mutations. The innovation of our strategy is to use the gamete (polar body or single sperm) as proband for single-nucleotide polymorphism (SNP) linkage analysis to detect an embryo's carrier status. Nine ADPKD couples with either de novo mutation or without a positive family history were recruited and a total of 34 embryos from 13 PGT-M cycles were examined. Within these nine couples, two successfully delivered healthy babies had their genetic status confirmed by amniocentesis. This study provides a creative approach for embryo diagnosis of patients with de novo mutations or patients who lack essential family members for linkage analysis., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Research Question: What is the incidence and origin of meiotic whole and segmental aneuploidies detected by karyomapping at a blastocyst stage in human-derived IVF embryos? What is the distribution of various types of errors, including rare chromosomal abnormalities?, Design: The incidence of chromosomal aneuploidies was assessed in 967 trophectoderm biopsies from 180 couples who underwent 215 cycles of IVF with preimplantation genetic testing for monogenetic disease with a known causal mutation with a mean maternal age of 32.7 years. DNA from both parents and a reference sample was genotyped together with the analysed trophectoderm samples by karyomapping (single-nucleotide-polymorphism-based array)., Results: Chromosomal abnormalities were detected in 31% of the analysed samples. At least one whole chromosomal aneuploidy was detected in 27.1% of the trophectoderm biopsies, whereas a segmental aneuploidy was detected in 5.1% of the trophectoderm biopsies. Our results reveal that segmental aneuploidies predominantly affect paternally derived chromosomes (70.4%; P < 0.01) compared with whole chromosomal aneuploidies that more frequently affect maternally derived chromosomes (90.1%; P < 0.0001). Also, the frequency of meiosis I (MI) and meiosis II (MII) errors was established in meiotic trisomies; MI errors were observed to be more frequent (n = 102/147 [69.4%]) than MII errors (n = 45/147 [30.6%])., Conclusions: Karyomapping is a robust method that is suitable for preimplantation genetic testing for monogenetic disease and for detecting meiotic aneuploidies, including meiotic segmental aneuploidies, and provides complex information about their parental origin. Our results revealed that segmental aneuploidy more frequently affects paternal chromosomes compared with whole chromosomal aneuploidy in human IVF embryos at the blastocyst stage., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To study the outcome of repeated biopsy for pre-implantation genetic testing in case of failed genetic diagnosis in the first biopsy., Methods: The study group included 81 cycles where embryos underwent re-biopsy because there were no transferable embryos after the first biopsy: in 55 cycles, the first procedure was polar body biopsy (PBs) and the second cleavage-stage (BB); in 26 cycles, the first was BB and the second trophectoderm (BLAST) biopsy. The control group included 77 cycles where embryos underwent successful genetic diagnosis following the first biopsy, matched by maternal age, egg number, genetic inheritance type, and embryonic stage at the first biopsy. We measured genetic diagnosis rate, clinical pregnancy rates (PRs), live-birth rates (LBRs), gestational age, and birth weight., Results: For repeated biopsy, genetic diagnosis was received in 67/81 cycles (82.7%); at a higher rate in PB + BB than in BB + BLAST (49/55, 89.1% and 18/26, 69.2% respectively, p = 0.055). Transferable embryos were found in 47 and 68 cycles in the study and the control groups. PRs/ET were 20/47 (42.6%) and 36/68 (52.9%) (p = 0.27), 16/36 (44.4%) following PB + BB, and 4/11 (36.4%) following BB + BLAST (p = 0.74). LBRs/ET were 13/47 (27.7%) in study group, and 28/68 (41.2%) in the controls (p = 0.14), 10/36 (27.8%) following PB + BB group, and 3/11 (27.3%) following BB + BLAST (p > 0.99). Gestational age and birth weight were similar in all groups., Conclusions: Re-biopsy of embryos when no genetic diagnosis could be reached following the first biopsy, achieved high rates of genetic diagnosis, pregnancies, and live births.

Purpose: The aim of this study was to determine the relationship between morphological parameters and the incidence of de novo chromosomal abnormalities. Methods: This was a retrospective cohort study of 652 patients who underwent 921 cycles with 3238 blastocysts biopsied. The embryo grades were evaluated according to Gardner and Schoolcraft's system. The incidence of euploidy, whole chromosomal aneuploidy (W-aneuploidy), segmental chromosomal aneuploidy (S-aneuploidy), and mosaicism in trophectoderm (TE) cell biopsies was analyzed. Results: The euploidy decreased significantly with maternal age and was positively correlated biopsy day and morphological parameters. The W-aneuploidy increased significantly with maternal age and was negatively correlated biopsy day and morphological parameters. Parental age, TE biopsy day, and morphological parameters were not associated with S-aneuploidy and mosaicism, except that TE grade C blastocysts had significantly higher mosaicism than TE grade A blastocysts. Subanalysis in different female age groups showed that euploidy and W-aneuploidy had a significant correlation with TE biopsy day among women aged ≤ 30 y and 31–35 y, with expansion degree among women aged ≥ 36 y, with ICM grade among women aged ≥ 31 y, and with TE grade among all female age ranges. Conclusion: Female age, embryo developmental speed and blastocyst morphological parameters are associated with euploidy and whole chromosomal aneuploidy. The predictive value of these factors varies across female age groups. Parental age, embryo developmental speed, expansion degree, and ICM grade are not associated with the incidence of segmental aneuploidy or mosaicism, but TE grade seemingly has a weak correlation with segmental aneuploidy and mosaicism in embryos. [ABSTRACT FROM AUTHOR]

Purpose: Women carriers of FMR1 premutation are at increased risk of early ovarian dysfunction and even premature ovarian insufficiency. The aim of this study was to examine a possible association between FMR1 permutation and numeric sex chromosome variations. Methods: A retrospective case-control study conducted in the reproductive center of a university-affiliated medical center. The primary outcome measure was the rate of sex chromosomal numerical aberrations, as demonstrated by haplotype analyses, in FMR1 premutation carriers compared to X-linked preimplantation genetic testing for monogenic/single gene defect (PGT-M) cycles for other indications that do not affect the ovarian follicles and oocytes. Results: A total of 2790 embryos with a final genetic analysis from 577 IVF PGT-M cycles were included in the final analysis. Mean age was similar between the groups, however, FMR1 carriers required more gonadotropins, and more women were poor responders with three or less oocytes collected. The ratio of embryos carrying a numeric sex chromosome variation was similar: 8.3% (138/1668) of embryos in the FMR1 group compared to 7.1% (80/1122) in the controls. A subgroup analysis based on age and response to stimulation has not demonstrated a significant difference either. Conclusions: Although carriers of FMR1 premutation exhibit signs of reduced ovarian response, it does not seem to affect the rate of numeric sex chromosomal variation compared to women undergoing PGT-M for other indications. This suggests that the mechanism for chromosomal number aberrations in women at advanced maternal age are different to those FMR1 premutation carriers with poor ovarian reserve. [ABSTRACT FROM AUTHOR]

The primary objective of preimplantation genetic testing for monogenic disorders (PGT-M) is to avoid having a child with a serious monogenic disease. Combining testing for unrelated sporadic chromosomal abnormalities (PGT-A) and excluding embryos with chromosomally abnormal results from transfer proffers the chance to mitigate the risk of miscarriage and to reduce the number of embryo transfers, but also risks excluding healthy embryos from transfer due to abnormal test results that do not reflect the true potential of the embryo. The theoretical utility of combining PGT-M with PGT-A is explored in this communication. It is concluded that PGT-M without PGT-A is preferred to achieve an unaffected live birth. Since PGT-M is mostly undertaken by couples where the female partner is younger than 35 years, PGT-A is likely to marginally mitigate the risk of miscarriage. Experimental non-selection studies are needed to assess the potential detrimental effect of combining PGT-M with PGT-A in a clinical setting. [ABSTRACT FROM AUTHOR]

Study Question: Can whole genome sequencing (WGS) offer a relatively cost-effective approach for embryonic genome-wide haplotyping and preimplantation genetic testing (PGT) for monogenic disorders (PGT-M), aneuploidy (PGT-A) and structural rearrangements (PGT-SR)?Summary Answer: Reliable genome-wide haplotyping, PGT-M, PGT-A and PGT-SR could be performed by WGS with 10× depth of parental and 4× depth of embryonic sequencing data.What Is Known Already: Reduced representation genome sequencing with a genome-wide next-generation sequencing haplarithmisis-based solution has been verified as a generic approach for automated haplotyping and comprehensive PGT. Several low-depth massively parallel sequencing (MPS)-based methods for haplotyping and comprehensive PGT have been developed. However, an additional family member, such as a sibling, or a proband, is required for PGT-M haplotyping using low-depth MPS methods.Study Design, Size, Duration: In this study, 10 families that had undergone traditional IVF-PGT and 53 embryos, including 13 embryos from two PGT-SR families and 40 embryos from eight PGT-M families, were included to evaluate a WGS-based method. There were 24 blastomeres and 29 blastocysts in total. All embryos were used for PGT-A. Karyomapping validated the WGS results. Clinical outcomes of the 10 families were evaluated.Participants/materials, Setting, Methods: A blastomere or a few trophectoderm cells from the blastocyst were biopsied, and multiple displacement amplification (MDA) was performed. MDA DNA and bulk DNA of family members were used for library construction. Libraries were sequenced, and data analysis, including haplotype inheritance deduction for PGT-M and PGT-SR and read-count analysis for PGT-A, was performed using an in-house pipeline. Haplotyping with a proband and parent-only haplotyping without additional family members were performed to assess the WGS methodology. Concordance analysis between the WGS results and traditional PGT methods was performed.Main Results and the Role Of Chance: For the 40 PGT-M and 53 PGT-A embryos, 100% concordance between the WGS and single-nucleotide polymorphism (SNP)-array results was observed, regardless of whether additional family members or a proband was included for PGT-M haplotyping. For the 13 embryos from the two PGT-SR families, the embryonic balanced translocation was detected and 100% concordance between WGS and MicroSeq with PCR-seq was demonstrated.Limitations, Reasons For Caution: The number of samples in this study was limited. In some cases, the reference embryo for PGT-M or PGT-SR parent-only haplotyping was not available owing to failed direct genotyping.Wider Implications Of the Findings: WGS-based PGT-A, PGT-M and PGT-SR offered a comprehensive PGT approach for haplotyping without the requirement for additional family members. It provided an improved complementary method to PGT methodologies, such as low-depth MPS- and SNP array-based methods.Study Funding/competing Interest(s): This research was supported by the research grant from the National Key R&D Program of China (2018YFC0910201 and 2018YFC1004900), the Guangdong province science and technology project of China (2019B020226001), the Shenzhen Birth Defect Screening Project Lab (JZF No. [2016] 750) and the Shenzhen Municipal Government of China (JCYJ20170412152854656). This work was also supported by the National Natural Science Foundation of China (81771638, 81901495 and 81971344), the National Key R&D Program of China (2018YFC1004901 and 2016YFC0905103), the Shanghai Sailing Program (18YF1424800), the Shanghai Municipal Commission of Science and Technology Program (15411964000) and the Shanghai 'Rising Stars of Medical Talent' Youth Development Program Clinical Laboratory Practitioners Program (201972). The authors declare no competing interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]