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Hemoglobinopathies are a group of autosomal recessive disorders characterized by either a reduced synthesis of one or more normal globin chains or the synthesis of a structurally abnormal globin chain or, in a few cases, by both that is, the reduced synthesis of a haemoglobin (Hb) variant. Depending on the mutations, these patients may exhibit distorted Hb patterns along with altered red cell indices, both of which can be used to support identification by diagnostic tools. The approach in the diagnosis of hemoglobinopathies and thalassemia depends upon the target geographical population and aim of testing. Red cell indices, Hb pattern analysis on high-performance liquid chromatography, and Hb capillary-zone electrophoresis are the first-line screening tests, and molecular testing helps confirm the diagnosis and is also useful in prenatal and preimplantation genetic diagnosis. Thalassemia patients need lifelong medical care, receiving trasfusions and supplemental therapies, and therefore, timely diagnosis and screening is essential. In the present paper, we review the potential pitfalls and interfering factors in their diagnosis. [ABSTRACT FROM AUTHOR]

The study assessed the direct medical costs of the cochlear implantation pathway from the healthcare payer's perspective, in children with bilateral severe to profound hearing loss, from diagnosis to 3 years' follow-up after first implantation. We also compared costs between two populations: congenital and progressive deafness. A retrospective costs analysis was performed for 56 children who received a cochlear implant in one French pediatric ENT center. The children had severe to profound hearing loss, and were implanted before the age of 10 years. We calculated direct medical costs in 3 phases: diagnosis to pre-implantation assessment, surgical and hospital management of implantation, and 3 years' follow-up. Mean costs were €64,675 (range, €38,709–113,954) per child from diagnosis to 3 years after first implantation. Mean costs in congenital deafness detected on neonatal screening and on progressive deafness were respectively €65,420 and €63,930 (P = 0.7). The global cost was €64,675 per child from diagnosis to 3 years after first implantation. There was no difference in cost according to congenital versus progressive hearing loss. [ABSTRACT FROM AUTHOR]

• PGCS has significantly reduced CF birth rates in Israel. • PGCS has led to a shift toward milder CF phenotypes. • Challenges remain in detecting rare variants and increasing PGCS utilization. Population genetic carrier screening (PGCS) for cystic fibrosis (CF) has been offered to couples in Israel since 1999 and was included in a fully subsidized national program in 2008. We evaluated the impact of PGCS on CF incidence, genetic and clinical features. This was a retrospective national study. Demographic and clinical characteristics of children with CF born in Israel between 2008 and 2018 were obtained from the national CF registry and from patients' medical records. Data on CF births, preimplantation genetic testing (PGT), pregnancy termination and de-identified data from the PGCS program were collected. CF births per 100,000 live births decreased from 8.29 in 2008 to 0.54 in 2018 (IRR = 0.84, p < 0.001). The CF pregnancy termination rate did not change (IRR = 1, p = 0.9) while the CF-related PGT rate increased markedly (IRR = 1.33, p < 0.001). One hundred and two children were born with CF between 2008 and 2018 with a median age at diagnosis of 4.8 months, range 0–111 months. Unlike the generally high uptake nationally, 65/102 had not performed PGCS. Even if all had utilized PGCS, only 51 would have been detected by the existing genetic screening panel. Clinically, 34 % of children were pancreatic sufficient compared to 23 % before 2008 (p = 0.04). Since institution of a nationwide PGCS program, the birth of children with CF decreased markedly. Residual function variants and pancreatic sufficiency were more common. A broader genetic screening panel and increased PGCS utilization may further decrease the birth of children with CF. [ABSTRACT FROM AUTHOR]

Heterozygous L1CAM variants cause L1 syndrome with hydrocephalus and aplasia/hypoplasia of the corpus callosum. L1 syndrome usually has an X-linked recessive inheritance pattern; however, we report a rare case occurring in a female child. The patient's family history was unremarkable. Fetal ultrasonography revealed enlarged bilateral ventricles of the brain and hypoplasia of the corpus callosum. The patient was born at 38 weeks and 4 days of gestation. Brain MRI performed on the 8th day of life revealed enlargement of the brain ventricles, marked in the lateral and third ventricles with irregular margins, and hypoplasia of the corpus callosum. Exome sequencing at the age of 2 years and 3 months revealed a de novo heterozygous L1CAM variant (NM_000425.5: c.2934_2935delp. (His978Glnfs * 25). X-chromosome inactivation using the human androgen receptor assay revealed that the pattern of X-chromosome inactivation in the patients was highly skewed (96.6 %). The patient is now 4 years and 11 months old and has a mild developmental delay (developmental quotient, 56) without significant progression of hydrocephalus. In this case, we hypothesized that the dominant expression of the variant allele arising from skewed X inactivation likely caused L1 syndrome. Symptomatic female carriers may challenge the current policies of prenatal and preimplantation diagnoses. [ABSTRACT FROM AUTHOR]

To evaluate whether insemination via intracytoplasmic sperm injection (ICSI) provides any benefit over in vitro fertilization (IVF) insemination for nonmale factor infertility with respect to preimplantation genetic testing (PGT) results and pregnancy outcome. Retrospective cohort study of the Society for Assisted Reproductive Technology database. US-based fertility clinics reporting to the Society for Assisted Reprodcutive Technology. Patients undergoing IVF or ICSI inseminations in nonmale factor PGT for aneuploidy cycles. In vitro fertilization vs. ICSI inseminations. Primary outcomes were the percentage of embryos suitable for transfer and live birth rates (LBRs). Secondary outcomes included subgroup analysis for embryos suitable for transfer on cycles from patients ≥35-year-old vs. <35-year-old, ≤6 oocytes retrieved vs. >6 oocytes retrieved, and unexplained infertility. Additionally, gestational age at delivery and birth weight between IVF and ICSI inseminations were evaluated. A total of 30,446 nonmale factor PGT diagnoses for aneuploidy cycles were evaluated, of which 4,867 were IVF inseminations and 25,579 were ICSI inseminations. Following exclusion criteria and adjustment for any necessary confounding variables, no significant differences existed in embryos suitable for transfer between IVF and ICSI treatment cycles, 41.6% (40.6%, 42.6%) vs. 42.5% (42.0%, 42.9%), respectively, or in LBRs, 50.1% (37.8, 62.4%) vs. 50.8% (38.5%, 62.9%), respectively. There were no significant differences in the rates of embryos suitable for transfer and LBRs between IVF and ICSI inseminations in nonmale factor cycles undergoing PGT for aneuploidy. [ABSTRACT FROM AUTHOR]

Pre-Implantation genetic diagnosis is available to couples at risk of conceiving a pregnancy affected with a known genetic disorder. Assisted reproductive techniques are used in combination with micromolecular diagnostic technologies to recognise at-risk embryos with pathogenic genetic variants at the pre-implantation stage using polar body, blastomere or trophectoderm biopsy. This review will discuss the varying genetic disorders diagnosed by Pre-Implantation Genetic Diagnosis, as well as the ethical, legal and safety implications of the process. Pioneering advances in molecular biology and cytogenomics have been utilised to expand the spectrum of genetic disorders detected. [ABSTRACT FROM AUTHOR]

The previous lack of national UK guidance on the use of Prenatal and Pre-implantation Genetic Testing (PND and PGT-M) for Monogenic Disorders for Germline Cancer Susceptibility Gene Variants (gCSGV) has led to disparities in care across the UK, and inequitable access to reproductive options for families living with cancer susceptibility syndromes. In 2023, the UK Cancer Genetics Group and Fetal Genomics Group of the British Society of Genetic Medicine developed joint consensus guidance seeking to provide healthcare professionals with a clear counselling framework to support individuals/couples during their reproductive decision-making process. The guidance is for healthcare professionals, individuals and couples with a gCSGV and their families, policy makers and charities supporting people with cancer susceptibility syndromes. Details about the consensus group participants, the main workshop's format, and the pre- and post-workshop nationwide surveys, are available in the full document. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the current evidence of pregnancy outcomes among couples with recurrent pregnancy loss (RPL) with abnormal karyotypes vs. those with normal karyotypes and among couples with RPL and abnormal karyotypes after receiving expectant management vs. preimplantation genetic diagnosis (PGD).Design: Systematic review and meta-analysis.Setting: Academic medical centers.Patient(s): Pregnancy outcomes in 6,301 couples with RPL who conceived without medical intervention in 11 studies were analyzed. However, only 2 studies addressed the outcomes of couples with RPL and abnormal karyotypes after expectant management (75 cases) vs. PGD (50 cases).Intervention(s): None.Main Outcome Measure(s): The pregnancy outcomes in couples with RPL with abnormal and normal karyotypes across included studies were evaluated.Result(s): Compared with those with a normal karyotype, a significantly lower first pregnancy live birth rate (LBR) was found in couples with RPL with abnormal karyotypes (58.5% vs. 71.9%; odds ratio [OR], 0.55; 95% confidence interval [CI], 0.46-0.65; I2 =27%). A markedly decreased first pregnancy LBR was found in couples with a translocation (52.9% vs. 72.4%; OR, 0.44; 95% CI, 0.31-0.61; I2 =33%) but not in couples with an inversion. However, the differences in accumulated LBR (81.4% vs. 74.8%; OR, 0.96; 95% CI, 0.90-1.03; I2 = 0) were nonsignificant, whereas the miscarriage rate was distinctly higher in couples with RPL and abnormal karyotypes (53.0% vs. 34.7%; OR, 2.21; 95% CI, 1.69-2.89; I2 = 0). Compared with those who chose expectant management, differences in accumulated LBR were nonsignificant (60% vs. 68%; OR, 0.55; 95% CI, 0.11-2.62; I2 =71%), whereas the miscarriage rate (24% vs. 65.3%; OR, 0.15; 95% CI, 0.04-0.51; I2 = 45) was markedly low in couples with RPL and abnormal karyotypes who chose PGD.Conclusion(s): Couples with RPL and abnormal karyotypes had a higher miscarriage rate than couples with normal karyotypes but achieved a noninferior accumulated LBR through multiple conception attempts. In couples with RPL and abnormal karyotypes, PGD treatment did not increase the accumulated LBR but markedly reduced miscarriage rate compared with expectant management. [ABSTRACT FROM AUTHOR]

Objective: To estimate the aneuploidy rates in young women with diminished ovarian reserve (DOR) before treatment and poor ovarian response (POR) postretrieval.Design: Retrospective cohort study.Setting: A single academically-affiliated fertility clinic.Patient(s): Autologous frozen embryo transfer cycles from December 2014 to June 2020 were reviewed. Demographic and clinical factors that impact outcomes were used for propensity score matching (PSM) in a ratio of 2:1 and 4:1 for preimplantation genetic testing for aneuploidy pre-cycle DOR and POR after stimulation, respectively.Intervention(s): None.Main Outcome Measure(s): Aneuploid rates, defined as the number of aneuploid blastocysts divided by the number of biopsied blastocysts per cycle. No euploid embryos to transfer, defined as all cohorts of embryos being aneuploid.Result(s): A total of 383 women diagnosed with DOR were compared with matched controls. Aneuploid rates did not differ significantly between the two groups (42.2% vs. 41.7%; RR = 1.06; 95% CI, 0.95-1.06). No differences were identified in live birth rates per transfer between women with and without DOR after euploid single-embryo transfers (56.0% and 60.5%, respectively). An additional PSM analysis to assess aneuploidy rates for patients with POR (<5 oocytes) vs. those without it, resulted in similar rates of aneuploidy between the two comparison groups (41.1% vs. 44%, R = 1.02; 95% CI, 0.91-1.14). The prevalence of cycles with "no euploid embryos" in the POR cohort was higher (26% vs. 13%); however, rates of cases with a single embryo available for biopsy were lower in the DOR group, relative to controls (11% vs. 31%).Conclusion(s): Young women diagnosed with DOR or POR exhibited equivalent aneuploidy rates and live birth rates per euploid embryo transfer in a large matched population, based on age, body mass index, and IVF cycle initiation. The lower percentage of cycles with no euploid embryo available for transfer in DOR and POR patients is because of the decreased total number of oocytes/developing embryos and not because of increased aneuploidy rates in these groups. [ABSTRACT FROM AUTHOR]

Objective: To determine the prognosis of patients who were only able to obtain aneuploid embryos in their first in vitro fertilization (IVF) cycle if they attempted a second cycle.Design: Case series and retrospective cohort study.Setting: A single, large fertility center.Patient(s): All patients who obtained only aneuploid embryos after IVF with preimplantation genetic testing for aneuploidy during the initial cycle and returned for a second cycle.Intervention(s): None.Main Outcome Measure(s): The percentage of patients who obtained a euploid embryo and live birth rates in the second cycle, stratified by Society for Assisted Reproductive Technology-defined age groups, was compared with that of controls from the same period.Result(s): A total of 538 patients with only aneuploid embryos in their first cycle were included. Three hundred (56%) patients obtained euploid blastocysts in the second cycle, with younger women having a higher chance of obtaining at least 1 euploid embryo (81% in women aged <35 years vs. 25% in women aged >42 years). The cumulative live birth rates were 71%, 62%, 46%, 27%, and 13% for the age groups <35, 35-37, 38-40, 41-42, and >42 years, respectively. The live birth rates per first embryo transfer were >57% across all the age groups and similar to those of the controls in the same age groups.Conclusion(s): Patients who obtained only aneuploid embryos during their initial IVF cycle retained favorable prognosis in their second cycle, with outcomes comparable with the national age-based standards. Younger women and those who had more embryos available for biopsy had the highest chance of success. These women should receive age-appropriate counseling and should not be discouraged from a second IVF attempt based on the results of their first cycle. [ABSTRACT FROM AUTHOR]

Research Question: The purpose of this study is to investigate whether the mitochondrial DNA (mtDNA) content can reflect the state of mosaic embryos.Design: The study included 1669 blastocysts derived from 394 PGT-A cycles between January 2018 and December 2020, in which preimplantation genetic testing for aneuploidy was performed and mtDNA content was determined. The standard deviation (SD) of whole genomic sequencing data was calculated for quality control. mtDNA content was measured as the proportion of mtDNA to genomic DNA. 1558 blastocysts with SD values less than 4.0 and mtDNA values less than 0.4% were selected for statistical analysis.Results: The mtDNA content of the PGT mosaic group was significantly higher than that of the PGT normal group (P < 0.001). Twenty-six mosaic embryos were transferred, and the results were as follows: 2 out of 26 had undergone a spontaneous miscarriage, 15 were not pregnant, and 9 resulted in a live birth. There were significant differences in the mtDNA content between the miscarriage/non-pregnancy group and the live birth group (**P < 0.01; ***P < 0.001). There was no mosaic embryo with more than 0.157% mtDNA content found in the live birth group.Conclusions: This study demonstrates that mtDNA analysis has the ability to identify mosaic embryos with high developmental potential. It can be a valuable supplementary index for the selection of mosaic embryos for transfer. Larger studies with a greater sample size will further our understanding of the relationships between metabolic activity and mosaicism. [ABSTRACT FROM AUTHOR]

Objective: To investigate if in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disease is cost effective for heterozygous individuals with Huntington disease vs. unassisted conception with prenatal diagnosis.Design: Cost-effectiveness analysis in a theoretical cohort of 3,851 couples, where one individual is heterozygous for Huntington disease.Setting: N/A.Patients/animals: None.Intervention: In vitro fertilization preimplantation genetic testing for couples attempting conception.Main Outcome Measures: Outcomes included cost and quality-adjusted life years (QALYs) for both parents in addition to secondary outcomes of procedure-related loss, spontaneous abortion, termination of pregnancy, and early/normal/late-onset Huntington disease. A willingness-to-pay threshold was set at $100,000/QALY.Results: In vitro fertilization preimplantation genetic testing is lower in cost and higher in effectiveness compared to unassisted conception with prenatal diagnosis among couples with one heterozygous Huntington disease individual, making it the dominant strategy. In vitro fertilization preimplantation genetic testing was associated with 77 more QALYs and a cost savings of $46,394,268. All measured outcomes were lower in the IVF preimplantation genetic testing strategy, including 39 fewer procedure-related losses, 39 fewer spontaneous abortions, and 462 fewer terminations of pregnancy. Most notably, in our theoretical cohort of couples, IVF preimplantation genetic testing resulted in 1,079 fewer Huntington disease-affected offspring. Our results were robust over a wide range of assumptions.Conclusion: In vitro fertilization preimplantation genetic testing is a cost-effective conception strategy compared to unassisted conception with prenatal diagnosis when one individual is heterozygous for Huntington disease. Not only can morbidity and mortality incurred by Huntington disease be mitigated for the offspring with the use of IVF preimplantation genetic testing, but this study demonstrates the cost-effectiveness of using IVF preimplantation genetic testing for those with Huntington disease. [ABSTRACT FROM AUTHOR]

The number and quality of embryos generated from the limited number of oocytes retrieved from low responders are important aspects of infertility treatment for these patients. This article focuses on 5 aspects relating to final maturation and laboratory techniques: follicular size at trigger, dual trigger, artificial oocyte activation (AOA), blastocyst transfer, and the role of preimplantation genetic testing for aneuploidy (PGT-A). There is lack of data regarding the role of follicular size, specifically in low-responder patients, but consideration should be given to using broader follicular size criteria when retrieving oocytes in this patient group. Use of dual trigger seems to be a good strategy in low-responder patients on the basis of initial evidence. Use of AOA with calcium ionophore may improve fertilization, embryonic development, and outcomes in cases with previous developmental problems. There is lack of data for low responders, but this promising technique deserves further study. In unselected patients, clinical trial data on blastocyst transfer are conflicting, and no high-quality studies have evaluated whether the live birth rate is higher after blastocyst transfer than after cleavage-stage embryo transfer in low responders. Specific evidence for PGT-A in low-responder patients is also lacking. Preimplantation genetic testing for aneuploidy should be considered in POSEIDON group 2 patients, especially those aged >38 years. Overall, applying the limited data available in combination with patient preference and individual patient characteristics will ensure a patient-centered and evidence-based approach that should optimize fertility outcomes for low responders. [ABSTRACT FROM AUTHOR]

Various biopsy and sampling methods are used for preimplantation genetic diagnosis (PGD) of embryo. This method benefits blastomer/trophectoderm biopsy to improve the clinical outcome of in vitro fertilization (IVF). However, all of these procedures are invasive and have adverse effects on embryo development. Additionally, these procedures require expensive equipment and well-experienced technicians. Regarding these limitations, designing non-invasive methods is necessary. One of the recently proposed non-invasive and applicable methods is cell free DNA (cfDNA) molecule evaluation that have opened up exciting opportunities in the molecular diagnosis of embryo and fetus chromosomal aneuploidy. cfDNA is present in body fluids; especially blood, follicular fluid, amniotic fluid, spent embryo culture medium (SCM) and blastocoel fluid. Overall, this review highlights the cfDNA biomarker might constitute a supplemental tool for improving IVF and pregnancy outcomes, female infertility management. However, the successful application of cfDNA demands an understanding of its biological properties, kinetics, time of collection, high sensitivity and specificity cfDNA detection methods, and their limitation and challenges in the clinical settings. In this review we also describe ethical aspects of cfDNA testing. [ABSTRACT FROM AUTHOR]

• A SCN patient harbors a c.248T > A ELANE mutation transmitted by paternal germline mosaicism. • Human cell lines with the specific mutation in the ELANE gene were generated. • CRISPR/Cas9-mediated gene editing was able to correct the mutation within the ELANE gene. Clinical and genetic characteristics of ELANE mutation of a 3-year-old male who had a severe congenital neutropenia (SCN) were examined. We then investigated whether CRISPR/Cas9-mediated gene editing could correct the mutation. The proband underwent extensive clinical assessments, such as exome sequencing and bioinformatics analysis, so that pathogenic genes could be identified. Sanger sequencing was also utilized for confirmation. The cell line, 293-ELANE, harboring ELANE mutation was generated, and the mutation was then corrected by CRISPR/Cas9-mediated homology-directed repair (HDR). The ELANE gene test in the proband unveiled a heterozygous de novo missense mutation: c. 248T > A (p.V83D), which was not detected in his asymptomatic parents who had provided peripheral blood samples. We found that 46.01% of his father's sperm cells had the same mutation. These results demonstrate that the proband inherited the ELANE mutation from his father, who had an average neutrophil count but had a germline mosaicism. The highest repair efficiency of CRISPR/Cas9-mediated HDR for 293-ELANE is 4.43%. We identified a missense mutation (p.V83D) in ELANE that causes SCN. This is the first report on paternal semen mosaicism of an ELANE mutation. Our study paves the way for preimplantation genetic diagnosis (PGD) based on ELANE mutation prevention and clinical treatment of congenital disabilities. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether preimplantation genetic testing (PGT) increases the risk of adverse obstetric and neonatal outcomes.Design: Systematic review and meta-analysis.Setting: Not applicable.Patient(s): Pregnancies achieved after PGT or in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).Intervention(s): Systematic search of databases until December 2020 with cross-checking of references from relevant articles in English.Main Outcome Measure(s): Obstetric and neonatal outcomes after PGT and IVF/ICSI, including mean birth weight, low birth weight, very low birth weight (VLBW), mean gestational age at birth, preterm birth, very preterm birth, birth defects, intrauterine growth retardation (IUGR), sex ratio, cesarean section, hypertensive disorders of pregnancy, gestational diabetes mellitus, placenta disorder (placenta previa, placenta abruption, placenta accreta), and preterm premature rupture of membranes.Result(s): Ultimately, a total of 785,445 participants were enrolled in this meta-analysis, and these participants were divided into a PGT group (n = 54,294) and an IVF/ICSI group (n = 731,151). The PGT pregnancies had lower rates of low birth weight (risk ratio [RR] 0.85, 95% confidence interval [CI] 0.75 to 0.98), VLBW (RR 0.52, 95% CI 0.33 to 0.81), and very preterm births (RR 0.55, 95% CI 0.42 to 0.70) than those of IVF/ICSI pregnancies. However, the PGT group had a higher rate of the obstetric outcome of hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.08 to 1.57). The PGT did not increase the risk of other adverse obstetric and neonatal outcomes, such as those associated with mean birth weight, mean gestational age at birth, birth defects, IUGR, sex ratio, cesarean section, gestational diabetes mellitus, placental disorder (placenta previa, placenta abruption, placenta accreta), or preterm premature rupture of membranes. We performed subgroup analysis with only blastocyst biopsies and found that PGT with blastocyst biopsies was associated with a lower rate of VLBW (RR 0.55, 95% CI 0.31 to 0.95). The PGT with blastocyst biopsies did not increase the risk of other adverse obstetric and neonatal outcomes. Additionally, we performed subgroup analysis with only frozen-thawed embryo transfer cycles, and we found that PGT pregnancies were associated with a lower rate of VLBW (RR 0.55, 95% CI 0.31 to 0.97), a lower rate of cesarean birth (RR 0.90, 95% CI 0.82 to 0.99), a higher rate of preterm birth (RR 1.10, 95% CI 1.02 to 1.18), and a higher rate of IUGR (RR 1.21, 95% CI 1.06 to 1.38) than those of IVF/ICSI pregnancies. The PGT with frozen-thawed embryo transfer did not increase the risk of other adverse obstetric and neonatal outcomes.Conclusion(s): The pooled analysis suggested that PGT did not increase the risk of adverse obstetric outcomes. The association between PGT and a higher risk of IUGR requires further investigation. [ABSTRACT FROM AUTHOR]

Objective: To apply long-read, third-generation sequencing as a part of a general workup strategy for performing structural rearrangement (PGT-SR) and monogenic disease (PGT-M) embryo testing.Design: Prospective study.Setting: In vitro fertilization unit.Patient(s): Couples presenting for PGT-SR (n = 15) and PGT-M (n = 2).Intervention(s): Blastocyst biopsy with molecular testing for translocation breakpoints or mutations (targets).Main Outcome Measure(s): Detailed, parental-phased, single-nucleotide polymorphism (SNP) profiles around targets for selection of informative polymorphic markers to simplify and facilitate clinical preimplantation genetic testing (PGT) designs that enable discrimination between carrier and noncarrier embryos.Result(s): High definition of chromosome breakpoints together with closely phased polymorphic markers was achieved for all 15 couples presenting for PGT-SR. Similarly, for the two couples presenting for PGT-M, tightly linked informative markers around the mutations were also simply identified. Three couples with translocations t(1;17)(q21;p13), t(3;13)(p25;q21.2), and t(12;13)(q23;q22) proceeded with PGT-SR, requesting preferential identification of noncarrier embryos for transfer. Following selection of a set of informative SNPs linked to breakpoints, we successfully performed PGT-SR tests, resulting in ongoing pregnancies with a noncarrier fetus for all couples. Similarly, with the use of tests based on informative SNPs linked to the parental mutations, one couple proceeded with PGT-M for maple syrup urine disease, resulting in an ongoing pregnancy with a disease-free fetus.Conclusion(s): For couples contemplating clinical PGT, variant haplophasing around the target reduces the workup process by enabling rapid selection of closely linked informative markers for patient-specific test design. [ABSTRACT FROM AUTHOR]

Objective: To assess the association between body mass index (BMI) and embryo aneuploidy and mosaicism in a cohort of patients undergoing in vitro fertilization (IVF) with trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) using next-generation sequencing technology.Design: Retrospective cohort study.Setting: Academic center.Patients: Patients undergoing their first IVF cycle with trophectoderm biopsy and PGT-A at our center between January 1, 2017, and August 31, 2020. Patients classified as underweight on the basis of BMI (BMI <18.5 kg/m2) and patients who underwent fresh embryo transfers were excluded.Intervention: None.Main Outcome Measures: Number and proportion of aneuploid, mosaic, and euploid embryos.Results: The patients were stratified according to the World Health Organization's BMI classification: normal weight (18.5-24.9 kg/m2, n = 1,254), overweight (25-29.9 kg/m2, n = 351), and obese (≥30 kg/m2, n = 145). Age-adjusted regression models showed no relationship between BMI classification and the number or proportion of aneuploid embryos. There were no statistically significant associations between BMI classifications and the number or proportion of mosaic or euploid embryos. A subgroup analysis of patients classified into age groups of <35, 35-40, and >40 years similarly showed no relationships between BMI and embryo ploidy outcomes.Conclusion: Body mass index was not associated with the number or proportion of aneuploid, mosaic, or euploid embryos in this large cohort of patients undergoing IVF with PGT-A, suggesting that the negative effect of excess weight on reproductive outcomes was independent of the ploidy status of the embryo cohort. [ABSTRACT FROM AUTHOR]

Objective: To provide full morphokinetic characterization of embryos ranked with different degrees of chromosomal mosaicism.Design: Retrospective cohort study.Setting: University-affiliated private in vitro fertilization clinic.Patient(s): We analyzed 1,511 embryos from 424 intracytoplasmic sperm injection cycles by culturing embryos in a time-lapse imaging system and performing next-generation sequencing. We assessed 106 mosaic embryos.Intervention(s): None.Main Outcome Measure(s): Comparison of chromosomal, morphological, and morphokinetic characteristics of blastocysts classified as euploid, aneuploid, low-degree mosaic (30% to <50% aneuploid cells in trophectoderm biopsy), and high-degree mosaic (50% to <70% aneuploid cells in trophectoderm biopsy). Statistical analysis was performed using χ2, Kruskal-Wallis, or analysis of variance tests according to data type and distribution. A two-way random effects model was used to calculate interoperator correlation of annotations, and a logistic mixed effects model was performed to evaluate the effect of confounders on morphokinetic timing.Result(s): The mosaicism rate was ∼7% regardless of parental age. Mosaicism and uniform aneuploidies were not evenly distributed across chromosomes. The percentage of high-quality blastocysts significantly decreased from euploid (66.9%) to mosaic (52.8%) and aneuploid (47.7%). Aneuploid blastocysts significantly delayed development compared with euploid blastocysts in start of compaction (median, 84.72 hours postmicroinjection [hpm], interquartile range [IQR], 13.2; vs. median, 82.10 hpm, IQR, 11.5), start of blastulation (median, 101 hpm; IQR, 11.7; vs. median, 98.29 hpm, IQR, 10.5), and timing of blastocyst (median, 108.04 hpm, IQR, 11.50; vs. median, 104.71 hpm, IQR, 11.35). However, embryo morphokinetics were not correlated to the degree of mosaicism or to a mosaicism configuration that was apt for embryo transfer.Conclusion(s): Morphokinetic timing of mosaic embryos overlaps with that of euploid and aneuploid embryos, which may reflect their unique genetic and developmental identity. Although this suggests mosaic embryos are not simply a misdiagnosis by-product, further studies are needed to reveal the true identity of this particular type of embryo. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of non-Robertsonian translocation with chromosome fusion (N-RBCF) on preimplantation embryos.Design: Case series.Setting: University-affiliated center.Patient(s): Twelve couples with N-RBCF.Intervention(s): Assisted reproduction with preimplantation genetic testing in chromosomal structural rearrangement (PGT-SR).Main Outcome Measure(s): Normal embryo rate, unbalanced translocation rate.Result(s): PGT was performed in 12 N-RBCF carriers, of whom 4 carried Y-autosome fusions and 8 autosomal fusions. A total of 12 (63.2%) of 19 blastocysts exhibited normal/balanced embryos, and only one (5.3%) embryo exhibited unbalanced translocations among Y-autosome fusion cases. In contrast to these findings, the percentage of normal/balanced blastocysts in 8 autosomal N-RBCF cases was 28.2% (11/39), whereas the unbalanced translocation rate was 53.8%. Furthermore, the percentage of normal/balanced embryos in the Robertsonian translocation group was significantly higher than that of the 8 autosomal N-RBCF (48.7% vs. 28.2%) cases. The rates of abnormality from chromosomal fusion in the 8 autosomal N-RBCF cases were significantly higher than those noted in the Robertsonian translocation (53.8% vs. 31.4%) subjects. The results of the stratified analysis according to the carrier's sex demonstrated that the rates of unbalanced translocation were significantly higher in the male autosomal N-RBCF subjects than those from the corresponding Robertsonian translocation (55% vs. 19.7%) cases.Conclusion(s): A low number of unbalanced translocations was identified in blastocysts from N-RBCF subjects who carried the Y fusion. The risk of unbalanced translocation in autosomal N-RBCF was higher than that of the Robertsonian translocation, notably in male carriers. [ABSTRACT FROM AUTHOR]

Pre-Implantation genetic diagnosis is available to couples at risk of conceiving a pregnancy affected with a known genetic disorder. Assisted reproductive techniques are used in combination with micromolecular diagnostic technologies to recognise at-risk embryos with pathogenic genetic variants at the pre-implantation stage using polar body, blastomere or trophectoderm biopsy. This review will discuss the varying genetic disorders diagnosed by Pre-Implantation Genetic Diagnosis, as well as the ethical, legal and safety implications of the process. Pioneering advances in molecular biology and cytogenomics have been utilised to expand the spectrum of genetic disorders detected. [ABSTRACT FROM AUTHOR]

• Novel complex heterozygous variations in HSPA9 causing Even-Plus syndrome were found. • The mutation spectrum leading to Even-Plus syndrome was expanded upon. • Genotype–phenotype relationships in early pregnancy were characterized. • A basis for future embryonic studies was provided. • Assisted reproductive technology was used to avoid transmission of the same mutation. Heat shock protein family A member 9 (HSPA9) prevents unfolded and dysfunctional protein accumulation, with genetic variants known to be pathogenic. Here, we determined the genetic cause of Even-Plus syndrome (OMIM: 616854) in a Chinese family. We collected samples from two affected and two normal individuals. Whole-exome sequencing was performed to identify their genetic profiles. Potential variants were validated using Sanger sequencing. Assisted reproduction with mutation-free embryos successfully blocked the transmission of mutations. We identified novel inherited pathogenic complex heterozygous variations in the HSPA9 gene in the two affected fetuses. Three-dimensional spatial simulation of the HSPA9 protein after prediction of the mutated RNA splicing pattern abolished part of the substrate-binding domain of the protein. According to ACMG guidelines, c. 1822-1G>A and c. 1411-3T>G were classified as pathogenic and likely pathogenic, respectively. Mutation-free embryos were selected for transplantation and reconfirmed to possess no mutations. A healthy daughter was successfully born into the family. This study is the first to report complex heterozygous variations in the HSPA9 gene that influence alternative splicing in early pregnancy. Our findings expand on the mutational spectrum leading to Even-Plus syndrome and provide a basis for genetic counseling and future embryonic studies. [ABSTRACT FROM AUTHOR]

Objective: To study how the attributes of mosaicism identified during preimplantation genetic testing for aneuploidy relate to clinical outcomes, in order to formulate a ranking system of mosaic embryos for intrauterine transfer.Design: Compiled analysis.Setting: Multi-center.Patient(s): A total of 5,561 euploid blastocysts and 1,000 mosaic blastocysts used in clinical transfers in patients undergoing fertility treatment.Intervention(s): None.Main Outcome Measure(s): Implantation (gestational sac), ongoing pregnancy, birth, and spontaneous abortion (miscarriage before 20 weeks of gestation).Result(s): The euploid group had significantly more favorable rates of implantation and ongoing pregnancy/birth (OP/B) compared with the combined mosaic group or the mosaic group affecting only whole chromosomes (implantation: 57.2% vs. 46.5% vs. 41.8%; OP/B: 52.3% vs. 37.0% vs. 31.3%), as well as lower likelihood of spontaneous abortion (8.6% vs. 20.4% vs. 25%). Whole-chromosome mosaic embryos with level (percent aneuploid cells) <50% had significantly more favorable outcomes than the ≥50% group (implantation: 44.5% vs. 30.4%; OP/B: 36.1% vs. 19.3%). Mosaic type (nature of the aneuploidy implicated in mosaicism) affected outcomes, with a significant correlation between number of affected chromosomes and unfavorable outcomes. This ranged from mosaicism involving segmental abnormalities to complex aneuploidies affecting three or more chromosomes (implantation: 51.6% vs. 30.4%; OP/B: 43.1% vs. 20.8%). Combining mosaic level, type, and embryo morphology revealed the order of subcategories regarding likelihood of positive outcome.Conclusion(s): This compiled analysis revealed traits of mosaicism identified with preimplantation genetic testing for aneuploidy that affected outcomes in a statistically significant manner, enabling the formulation of an evidence-based prioritization scheme for mosaic embryos in the clinic. [ABSTRACT FROM AUTHOR]

Objective(s): To determine whether women with diminished ovarian reserve (DOR) (quantitatively) had lower rates of euploid blastocysts, as a proxy for oocyte quality.Design: Retrospective cohort study.Setting: University reproductive health clinic.Patient(s): A total of 1,152 women aged 19-42 years underwent 1,675 IVF cycles yielding 8,073 blastocysts for biopsy from 2010 to 2019.Interventions(s): Preimplantation genetic testing for aneuploidy.Main Outcome Measure(s): Euploid rates, defined as the number of euploid blastocysts divided by the number of biopsied blastocysts per cycle.Result(s): A total of 225 women (20%) had DOR as infertility diagnosis per the Bologna criteria. Age was higher among the women with DOR (39.5 y vs. 37.0 y). Euploid rates were lower among women with vs. without DOR (29.0% vs. 44.9%). In generalized linear models controlling for age, women with DOR had 24% reduced odds of a biopsied blastocyst being euploid versus women without DOR. In a secondary analysis assigning DOR status to women producing the lowest quartile of age-adjusted mature oocyte yield, this relationship remained. No differences were identified in live birth rates between women with and without DOR after euploid single-embryo transfer independently from age (n = 944 transfers; 56.8% vs. 54.8%, respectively).Conclusion(s): Blastocysts from women with DOR are less likely to be euploid than those from women without DOR after adjustment for age. Given the concomitant reduction in euploid rates with quantity of oocytes observed in this study, quantitative ovarian reserve assessments (i.e., follicular machinery) may yield insight into relative ovarian aging. [ABSTRACT FROM AUTHOR]

Disorders affecting the sperm, oocyte, or embryo may cause a significant fraction of spontaneous miscarriages and cases of recurrent pregnancy loss (RPL). Altered chromosomal integrity of sperm and oocytes, which is highly dependent of the age of the mother, represents a major cause of miscarriage and in turn RPL. Avoiding transfers of abnormal embryos is possible with preimplantation genetic testing for aneuploidies. Chromosomal anomalies may also be caused by structural rearrangements of one or several chromosomes in either parents, a finding encountered in 12% of couples with RPL, including in those who have had one or several healthy babies. More than 40% of these chromosomal rearrangements are identifiable on regular karyotypes. When abnormal findings are made, preimplantation genetic testing for monogenic disorders allows selection of disease-free embryos. Finally, asymmetric inactivation of the X chromosome has been found more commonly in women with RPL, but no specific treatment is currently available. [ABSTRACT FROM AUTHOR]

Objective: To determine the predictive value of an aneuploid diagnosis with a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy (PGT-A) assay in prognosticating the failure of a successful delivery.Design: Prospective, blinded, multicenter, nonselection study. All usable blastocysts were biopsied, and the single best morphologic blastocyst was transferred before genetic analysis. Preimplantation genetic testing for aneuploidy was performed after clinical outcome was determined. Clinical outcomes were compared to PGT-A results to calculate the predictive value of a PGT-A aneuploid diagnosis.Setting: Fertility centers.Patient(s): Couples undergoing their first in vitro fertilization cycle without recurrent pregnancy loss, antral follicle count < 8, or body mass index ≥ 35 kg/m2.Intervention(s): None.Main Outcome Measure(s): The primary outcome was the ability of the analytical result of aneuploid to predict failure to deliver (clinical result). A secondary outcome was the impact of the trophectoderm biopsy on sustained implantation.Result(s): Four hundred two patients underwent 484 single, frozen, blastocyst transfers. The PGT-A aneuploid diagnosis clinical error rate was 0%. There was no difference in sustained implantation between the study group and an age-matched control group, where biopsy was not performed (47.9% vs. 45.8).Conclusion(s): The PGT-A assay evaluated was highly prognostic of failure to deliver when an aneuploid result was obtained. Additionally, the trophectoderm biopsy had no detectable adverse impact on sustained implantation.Clinical Trial Registration Numbers: NCT02032264 and NCT03604107. [ABSTRACT FROM AUTHOR]

Recent advancements in reproductive genetics have resulted in the availability of an extraordinary amount of new and detailed information for patients and providers. Whereas this information can inform many who are facing difficult clinical decisions, it can also introduce complex and uncertain choices. Expanded carrier screening and preimplantation genetic diagnosis for aneuploidy are important examples of new genetic techniques that are now widely used in reproductive medicine. This paper will explore these techniques through a medical-legal prism to better understand the opportunities and obligations incumbent on both patients and providers in this new age of genetic diagnosis. [ABSTRACT FROM AUTHOR]

Research question: Does newborn gender affect placental histopathology pattern and perinatal outcome in singleton live births following IVF treatment? Design: Retrospective cohort study evaluating data of all live births from one academic tertiary hospital following IVF treatment during 2009–2017. All patients had placentas sent for pathological evaluation irrelevant of maternal and fetal complications status. Exclusion criteria were abnormal uterine cavity findings, previous uterine surgery, in-vitro maturation cycles, gestational carrier cycles, oocyte recipient cycles, preimplantation genetic diagnosis cycles and multiple pregnancies. The primary outcomes included anatomical, inflammation, vascular malperfusion and villous maturation placental features. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate analysis was conducted to adjust the results for factors potentially associated with placental pathology features. Results: A total of 1057 live births were included in the final analysis and were allocated to the study groups according to fetal gender: males (n = 527) and females (n = 530). After adjustment for potential confounding factors, male gender was significantly associated with villous agglutination (odds ratio [OR] 9.8; 95% confidence interval [CI] 1.4–78.2), avascular villi (OR 4.1; 95% CI 1.3–12.6) and maternal vascular malperfusion (OR 1.8; 95% CI 1.2–2.7). Female gender was significantly associated with bilobed placenta (OR 0.2; 95% CI 0.06–0.8) and subchorionic thrombi (OR 0.5; 95% CI 0.3–0.9). The prevalence of adverse fetal, maternal and delivery outcomes was similar between the groups. Conclusions: Newborn gender has a significant impact on the placental histopathology pattern, which can contribute to the development of adverse perinatal outcomes. [ABSTRACT FROM AUTHOR]

Objective: To determine the rate of utilization, factors influencing the decision-making process, and patient satisfaction with preimplantation genetic diagnosis for monogenic disorders (PGT-M).Design: Survey study.Setting: Academic center.Patient(s): Genetically at-risk patients seen for PGT-M consultation between January 2010 and 2018.Intervention(s): Electronic survey including demographics, genetic history, consultation experience, decision-making process, and satisfaction with PGT-M process.Main Outcome Measure(s): Rate of utilization of PGT-M, importance of decision-making factors, and satisfaction with PGT-M process.Result(s): Among survey respondents (n = 49), the rate of utilization of PGT-M after consultation was 89.8%. Ninety-three percent of participants decided whether to pursue PGT-M within 3 months of consultation. Factors that were considered most important to this decision-making process included information provided at consultation, accuracy of test results after PGT-M, avoidance of suffering of an affected child, and ability to avoid termination of an affected pregnancy. Key barriers to utilization included financial burden and overall complexity of the in vitro fertilization (IVF)/PGT-M process. Of those utilizing PGT-M (n = 44), 72.1% had at least one live birth or were pregnant during the study period. Satisfaction with PGT-M was high, and most couples would use IVF/PGT-M for a future pregnancy (84.1%). Participants with a live birth were more satisfied with the PGT-M process than those who had no live birth.Conclusion(s): Most patients seeking consultation for PGT-M were likely to pursue this technology despite financial burden and complexity of the process. Exploring factors that influence patient decision-making regarding PGT-M is important for tailoring the consultation and optimizing the overall experience. [ABSTRACT FROM AUTHOR]

Objective: To assess whether trophectoderm biopsy has any impact on the level of serum β-human chorionic gonadotropin (β-hCG) in early pregnancies.Design: Retrospective cohort study.Setting: University-affiliated reproductive medical center.Patient(s): Three hundred and eighty-three women undergoing 396 frozen embryo transfer (FET) cycles with preimplantation genetic testing (PGT), and 353 women undergoing 465 FET cycles with in vitro fertilization or intracytoplasmic sperm injection, all women having positive serum β-hCG results on the 12th day after blastocysts transfers.Intervention(s): None.Main Outcome Measure(s): Serum β-hCG levels on the 12th day after warmed blastocyst transfer and perinatal outcomes of clinical pregnancy.Results: The diagnostic threshold of serum β-hCG levels on the 12th day after FET for prediction of a live birth was 368.55 mIU/mL with an area under the curve of 0.791 (0.729∼0.853) in the biopsy group, which was lower than the 411.45 mIU/mL in the control group. The average level of serum β-hCG in the biopsy group with clinical pregnancies was statistically significantly lower than that of the control group: 703.10 (569.63) versus 809.20 (582.00), respectively. No statistically significant differences in perinatal outcomes, including gestational age, hypertensive disorder in pregnancy, and neonatal malformation, were found between the two groups.Conclusion(s): Trophectoderm biopsy may reduce the level of serum β-hCG in early pregnancies (the 12th day after embryo transfer), but no increased risk was found of adverse perinatal outcomes after trophectoderm biopsy. [ABSTRACT FROM AUTHOR]

Objective: To describe the outcome of preimplantation genetic testing (PGT-A) using their own oocytes in patients with mosaic Turner Syndrome (MTS). The impact of the assisted reproduction technique (ART) performed (PGT-A or oocyte donation) and the type of absence of the X chromosome (total or partial) were considered.Design: Retrospective observational multicenter study.Setting: University-affiliated private in vitro fertilization center.Patient(s): Fifty-six patients with MTS with whom 65 ovarian stimulation cycles for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) were performed. The study included 90 women with MTS and 20 women with pure Turner Syndrome (PTS) who underwent 140 and 25 oocyte donation (OD) cycles, respectively.Intervention(s): In vitro fertilization for PGT-A (fluorescence in situ hybridization/arrays-next generation sequencing) or OD.Main Outcome Measure (s): Reproductive outcome and feto-maternal outcomes.Results: The live birth rate (LBR) per embryo transfer in patients with MTS tended to be higher in OD 37.7% (95% confidence interval [CI]: 29.3-46.1) than that observed for PGT-A 22.5% (95% CI 7.8-38.2), and the cumulative LBR (CLBR), with 77.6% vs. 43.3%, respectively. Likewise, the LBR per patient was significant when comparing PGT-A vs. OD, with 12.5% (95 CI 3.9-21.1) vs. 51.1% (40.7-61.4), respectively. While focusing on the X chromosome, partial MTS (PTS), we found significant differences in the CLBR per embryo transfer, with 77.6% vs. 29.2%, and also in the LBR per patient: 51.1% (40.7-61.4) in MTS vs. 15% (95 CI 0.0-30.1) in PTS.Conclusion(s): Oocyte donation is the best reproductive option in females with Turner Syndrome with or without mosaicisms. Nevertheless, PGT-A is a valid therapeutic option in patients with MTS using their own oocytes, and OD should not necessarily be directly recommended. [ABSTRACT FROM AUTHOR]

Objective: To investigate a possible correlation between chromosomal aberrations and paternal age, analyzing embryos derived from young oocyte donors, with available preimplantation genetic testing for aneuploidy results from day 5/6 trophectoderm biopsy obtained by next-generation sequencing for all 24 chromosomes.Design: Retrospective cohort study.Setting: Canadian fertility centre.Patient(s): A total of 3,118 embryos from 407 male patients, allocated into three paternal age groups: group A, ≤39 years (n = 203); group B, 40-49 years (n = 161); group C, ≥50 years (n = 43).Intervention(s): None.Main Outcome Measure(s): The primary outcomes were aneuploidy, euploidy, mosaicism, and blastocyst formation rates. Secondary endpoints were comparison of specific chromosome aneuploidy, segmental and complex (involving two chromosomes + mosaicism >50%) aneuploidy, and analysis of overall percentage of chromosomal gains and losses within each group.Result(s): The study included 437 in vitro fertilization (IVF) antagonist cycles using 302 oocyte donors in which preimplantation genetic testing for aneuploidy was performed. Overall, 70.04% of embryos were euploid, 13.9% were aneuploid, and 16.06% were mosaic. No significant differences among paternal age groups A, B, and C were found in euploidy rates (69.2%, 70.6%, 71.4%, respectively), aneuploidy rates (14.7%, 12.8%, 13.9%, respectively) or mosaicism rates (16.1%, 16.6%, 13.6%; respectively). The fertilization rate was lower in group C compared with group B (76.35% vs. 80.09%). No difference was found in blastocyst formation rate between the study groups (median 52% [interquartile range, 41%, 67%] vs. 53% [42%, 65%] vs. 52% [42%, 64%], respectively). A generalized linear mixed model regression analysis for embryo ploidy rates found older oocyte donor age to be independently associated with embryo aneuploidy (odds ratio = 1.041; 95% CI, 1.009-1.074). The rate of segmental aneuploidies was significantly higher in the older versus younger paternal age group (36.6% vs. 19.4%).Conclusion(s): No association was found between paternal age and aneuploidy rates in embryos derived from IVF cycles using young oocyte donors, after adjusting for donor, sperm, and IVF cycle characteristics. Advanced paternal age ≥ 50, compared with younger paternal ages, was associated with a lower fertilization rate and increased rate of segmental aberrations. [ABSTRACT FROM AUTHOR]

Embryo diagnostics are somewhat controversial in clinical assisted reproduction technology (ART) practice and remain an active area of investigation. Application of embryo diagnostics holds great potential to raise the standard of clinical care by eliminating futile transfers, allowing highly effective single-embryo transfer, and reducing the probability of clinical loss and ongoing abnormal gestations. These advantages are accompanied by risks, principally the chance that a reproductively competent embryo will be mislabeled and discarded. This would lower the ultimate probability that one or more of the embryos might implant and lead to delivery of a healthy infant. Rigorous validation should be required for embryo diagnostics. Metrics for validation can be divided into three simple areas: analytical validation, determination of clinical predictive values for normal and abnormal test results, and a randomized clinical trial to demonstrate that the selection advantage gained through the diagnostic improves clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: To compare two different blastocyst biopsy protocols.Design: Retrospective single-center cohort study.Settings: Private in vitro fertilization center.Patient(s): The study included 1,670 frozen-thawed embryo transfers (FETs) with preimplantation genetic testing for aneuploidy (PGT-A).Intervention: None.Main Outcome Measure(s): Survival rate (SR) after thawing, clinical pregnancy rate (CPR), ongoing implantation rate (IR), and live birth rate (LBR).Result(s): Eight hundred thirty-five FETs with PGT-A cycles including only embryos biopsied in the sequential blastocyst hatching and biopsy protocol paired with the ablation of one-fourth of the zona pellucida (ZP) were matched with 835 FETs with PGT-A cycles including only embryos biopsied in the day 3 prehatching protocol by female age (±1 year), number of embryos transferred, use of gestational carrier or egg donor, and day of blastocyst transfer. Only FETs with euploid blastocysts graded no lower than 4BB were included, and cycles with fewer than five oocytes were excluded. SR after thawing, CPR, ongoing IR, and LBR were significantly higher in the FET cycles with the embryos biopsied in the sequential hatching and biopsy protocol. Four cases of monozygotic twin pregnancies were reported with the day 3 prehatching protocol and none with the sequential hatching and biopsy protocol.Conclusion(s): Our results show, for the first time, that using different blastocyst biopsy protocols can affect clinical outcomes. Because the study was retrospective, our findings should be validated in a prospective trial. [ABSTRACT FROM AUTHOR]

Objective: To assess whether the calculated difference in endometrial thickness from the end of the estrogen phase to the day of ET (after 6 days of P in hormonally prepared cycles) is associated with ongoing pregnancy rates in euploid frozen ETs (FETs).Design: An observational cohort study.Setting: Single tertiary care medical center.Patient(s): Ultrasound images from 234 hormonally prepared FET cycles were assessed. All the transfers were elective single ETs of a euploid embryo, post-preimplantation genetic testing for aneuploidy (PGT-A).Intervention(s): Ultrasound measurements of peak endometrial thickness at the end of the estrogen phase and again after 6 days of P at the time of ET.Main Outcome Measure(s): Ongoing pregnancy rate in relation to the delta between endometrial thickness at the end of estrogen phase and at the time of ET.Result(s): We calculated the ongoing pregnancy rate in cycles where the endometrial lining decreased (compacted) after addition of P by 5%, 10%, 15%, and 20% and demonstrated a significantly higher pregnancy rate after all rates of compaction of the endometrial lining in comparison with cycles where the endometrial lining did not compact. The ongoing pregnancy rate in this cohort, after compaction of 15% or more, was 51.5%, compared with 30.2% in cycles where the endometrial lining did not compact.Conclusion(s): There is a significant correlation between endometrial lining compaction and ongoing pregnancy rate in FET cycles of euploid embryos. These findings help to explain why some euploid embryos may fail to implant. [ABSTRACT FROM AUTHOR]

What are the incidence and patterns of meiotic trisomies and recombination separately and in relation to each other at the blastocyst stage via single nucleotide polymorphism genotyping combined with array comparative genomic hybridization. Single nucleotide polymorphism microarrays were carried out on a total of 1442 blastocyst stage embryos derived from 268 fertile couples undergoing preimplantation genetic diagnosis for the purposes of avoiding transmittance of known single gene disorders to their offspring; 24-chromosome aneuploidy screening via array comparative genomic hybridization was carried out in parallel. One hundred per cent of meiotic trisomies identified in these embryos were of maternal origin and their incidence increased significantly with advancing maternal age (P < 0.0001). A total of 55.8% of meiotic trisomies were meiosis I-type and 44.2% were meiosis II-type. Certain chromosomes were affected more by meiosis I-type errors, whereas others experienced more meiosis II-type errors. A detailed recombination analysis was carried out for 11,476 chromosomes and 17,763 recombination events were recorded. The average number of recombination sites was 24.0 ± 0.3 for male meiosis and 41.2 ± 0.6 for female meiosis (autosomes only). Sex-specific differences were observed in the locations of recombination sites. Comparative analysis conducted between 190 euploid embryos and 69 embryos presenting maternal meiotic trisomies showed similar recombination rates (P = 0.425) and non-recombinant chromatid rates (P = 0.435) between the two categories; differences, however, were observed when analysing embryos affected with specific maternal meiotic trisomies. This study yielded unique data concerning recombination and the origin of aneuploidies observed during the first few days of life and provides a novel insight into these important biological processes. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the incidence of chromosomal abnormalities in blastocysts is higher in patients with idiopathic recurrent pregnancy loss (iRPL) who underwent preimplantation genetic testing for aneuploidy (PGT-A) than in those who underwent preimplantation genetic testing for monogenic defects (PGT-M).Design: Retrospective cohort study.Setting: University-affiliated reproductive center.Patient(s): A total of 62 patients with iRPL underwent 101 PGT-A cycles (iRPL group), and 212 patients underwent 311 PGT-M cycles (control group).Interventions(s): Blastocyst biopsy and comprehensive chromosome screening technologies, including single-nucleotide polymorphism microarrays and next-generation sequencing.Main Outcome Measure(s): Incidence of chromosomal abnormalities in blastocysts and clinical miscarriage (CM) rate.Result(s): Stratification analysis by maternal age showed an increased incidence of chromosomal abnormalities in the iRPL group aged ≤35 years (48.9% vs. 36.9%), whereas no significant increase was found in the iRPL group aged >35 years (66.9% vs. 61.4%). After transfer of euploid embryos, women aged ≤35 years with iRPL exhibited an increased CM rate compared with the control group (26.1% vs. 3.1%).Conclusion(s): Young patients with iRPL have a significantly higher rate of chromosomal abnormalities in blastocysts compared with patients with no or sporadic CM. Although euploid embryos were transferred after PGT-A, young patients with iRPL had a higher CM rate, which may indicate that chromosomal abnormalities might not be the only causal factor for iRPL. Therefore, the role of PGT-A in iRPL still needs to be clarified. [ABSTRACT FROM AUTHOR]

While the goals of genetic counseling for cystic fibrosis – delivering relevant information on the risk of recurrence and nondirectional support of couples at risk in their reproductive choices – have not changed fundamentally, the practice has evolved considerably in the last decade, growing more complex to face new challenges but also proving more effective. Many factors have contributed to this evolution: technical progress in the exploration of the genome (new generation sequencing) and in reproductive medicine, but also societal developments promoting access to genetic information and the professionalization of genetic counselors in France. The prospect of expanded pre-conception screening of at-risk couples makes genetic counselors major actors not only in medical care centers, but also in modern society by contributing to genetic education among citizens. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved. [ABSTRACT FROM AUTHOR]

Objective: To investigate the use of preimplantation genetic testing for aneuploidy (PGT-A) among patients pursuing embryo banking (EB) for medically indicated fertility preservation (FP).Design: Retrospective cohort.Setting: University-affiliated fertility center.Patients: All patients who underwent in vitro fertilization with or without PGT-A for medically indicated FP between January 2014 and April 2018.Interventions: None MAIN OUTCOME MEASURES: EB cycle characteristics, subsequent cycle pursuit/outcomes, and frozen embryo transfer (FET) outcomes.Results: A total of 58 medical EB cycles were compared; 34 cycles used PGT-A. Of the EB patients with breast cancer, 67% used PGT-A; other indications were evenly divided between PGT-A (FP/PGT-A) and no PGT-A (FP). PGT-A use increased over the study period. Groups were similar in age, days of stimulation, and days from initial FP consultation to treatment initiation. Number of oocytes (14.5 [2-63] FP vs. 17.5 [1-64] FP/PGT-A), 2PN zygotes (7 [1-38] FP vs. 9 [0-36] FP/PGT-A), and blastocysts (5.5 [0-22] FP vs. 5 [0-18] FP/PGT-A) cryopreserved were similar between groups. Equal numbers cryopreserved both oocytes and embryos (5 vs. 3). Five FP/PGT-A patients underwent a second EB cycle. Among FP/PGT-A patients, an average of 6.7 ± 5 blastocysts underwent PGT-A, with 3.5 ± 3 (48.2%) euploid embryos cryopreserved for future FET compared to an average of 7.2 ± 7 untested embryos in the FP group.Conclusion: PGT-A in medical EB cycles increased over time and did not limit the use of other FP methods such as oocyte cryopreservation. In some cases, poor PGT-A results informed patients to pursue a second EB cycle. When counseling patients, the prognostic benefits of PGT-A must be weighed against the financial costs and potential for "terminal" fertility diagnosis. [ABSTRACT FROM AUTHOR]

The recent introduction of polygenic risk scores within preimplantation genetic testing (PGT-P) has been met with many concerns. To get more insights into the perspectives of relevant stakeholders on the socio-ethical aspects of PGT-P, an interview study with 31 healthcare professionals involved in reproductive medicine and genetics in Europe and North-America was performed. Healthcare professionals in our study were concerned that PGT-P was going too far in terms of selection, with regards to both medical conditions and non-medical traits. Healthcare professionals were worried about the ethical 'slippery slope' of PGT-P, the increasing medicalization of reproductive health, the commercial context of PGT-P, and potential stigmatization and discrimination. There were also concerns that the availability and the 'technological imperative' of PGT-P could lead to pressure and a sense of responsibility for parents to use PGT-P. Additionally, it could cause new anxieties about the child's health before the child has even been born. Since PGT-P provides polygenic risk scores before birth, the autonomy of the child has to be considered. These socio-ethical concerns heighten existing debates regarding reproductive genetic technologies and show that the specifics of PGT-P make this screening option especially ethically controversial. • Introduction of polygenic risk scores in preimplantation genetic testing. • Healthcare professionals concerned about socio-ethical implications. • Associated with 'slippery slope', going too far, discrimination and stigmatization. • Increased sense of medicalization and commercialization of reproduction and health. • Worries about effects on prospective parents and on the future child's autonomy. [ABSTRACT FROM AUTHOR]

• Conceiving a saviour sibling can be a viable treatment option but its legality may be questioned where there are no clear laws or policies. • In Malaysia, the only guidance appears to be the Guideline issued by the Malaysian Medical Council which does not explicitly state the position of this practice. • Previous literature has construed the Guideline narrowly. • This paper suggests a more meaningful approach to interpret the Guideline which should take into account the guiding principles of the Guideline, the nature of the technology, its implication and intended use. Conceiving a saviour sibling can be a vital treatment option for a child suffering from a haematological condition. However, the legality of this option may be called into question in countries where there is no clear law or policy regarding the use of preimplantation genetic diagnosis with HLA typing (PGD-HLA typing) or HLA typing alone for this purpose. In Malaysia for instance, there is no legislative framework governing the use of assisted reproductive technology and the only guidance appears to be provided by guidelines issued by the Malaysian Medical Council. In the absence of clear direction, broad guidelines or policy positions taken by such statutory bodies may heavily influence the practice or roll out of certain technologically advanced therapeutic interventions. Previous literature has construed this Guideline narrowly as prohibiting this practice. This paper argues that the narrow and traditional interpretation method used in previous literature is wanting and suggests a more meaningful approach to the interpretation of the Guideline and advocates that this interpretative method should be applied in similar instances involving technologically advanced treatment modalities in other similar situations. Such guidance documents should be interpreted in a manner which takes into account the nature of the technology, its implications and intended use. [ABSTRACT FROM AUTHOR]

Objective: To evaluate differences in euploidy rates between IVF cycles triggered with either GnRH agonist (GnRHa) or hCG.Design: Retrospective cohort study.Setting: University-affiliated fertility center.Patient(s): A total of 366 patients performing 539 IVF cycles utilizing preimplantation genetic testing for aneuploidy (PGT-A).Intervention(s): Gonadotropin-releasing hormone agonist or hCG trigger of oocyte maturation during IVF cycles.Main Outcome Measure(s): Rate of euploid embryos.Result(s): Patients in the GnRHa trigger arm were younger, with a lower body mass index and higher antimüllerian hormone level, and they had a higher number of oocytes retrieved and embryos biopsied. Euploid rate per embryo biopsied was higher after GnRHa trigger than after hCG trigger (37.8% ± 2.1% vs. 30.3% ± 1.8%), but multivariate regression analysis controlling for potential confounding factors did not show any differences between the two groups. Moreover, the euploid rate per oocyte retrieved was not significantly different overall (GnRHa vs. hCG: 33.9% ± 2.2% vs. 28.0% ± 1.9%). The anticipated decline in the rate of euploid embryos per oocyte retrieved went from 15.8% ± 1.2% for age <35 years to 4.3% ± 0.9% for patients aged ≥41 years. There were no significant differences between the two groups after stratifying by age and controlling for PGT-A testing modality.Conclusion(s): Both GnRHa and hCG trigger result in comparable euploid rates. Trigger with GnRHa should therefore be considered a valid option for trigger modality in freeze-all PGT-A cycles, in view of its demonstrated effectiveness and known safety enhancement. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether blastocyst biopsy in preimplantation genetic testing (PGT) increases the risk of adverse neonatal outcomes.Design: Retrospective cohort study.Setting: University-affiliated center.Patients: Live births after blastocyst biopsy combined with frozen ET (PGT group) and frozen blastocyst transfer after in vitro fertilization or intracytoplasmic sperm injection (control group).Intervention(s): Blastocyst biopsy.Main Outcome Measure(s): Gestational age (GA), birth weight (BW), and rates of preterm birth (PB), very preterm birth (VPB), extreme preterm birth (EPB), low birth weight (LBW), very low birth weight (VLBW), and macrosomia.Result(s): No significant differences were observed in the sex ratio, GA, PB, VPB, EPB, BW, or rates of LBW, VLBW, and macrosomia between the PGT and control groups for either singletons or twins. However, the cesarean section rate of the PGT group was significantly higher than that of the control group for twins (adjusted odds ratio, 2.383 [1.079, 5.259]). Regarding fluorescence in situ hybridization-PGT neonates, neonatal outcomes, including GA, BW, and rates of PB, VPB, LBW, and VLBW, did not differ between the different groups of biopsied cells (≥10 group and <10 group) for either the grade B or grade C trophectoderm score subgroups; however, in the grade B trophectoderm score subgroup, the rate of boy babies in the ≥10 group was significantly higher than that in the <10 group (83.3% vs. 40.9%). The association between the number of biopsied cells and GA/BW was not statistically significant.Conclusion(s): Blastocyst biopsy may not add additional risk to neonatal outcomes when compared with a control group. [ABSTRACT FROM AUTHOR]

Objective: To investigate the developmental potential of oocytes and embryos derived from extremely small follicles (<10 mm) in comparison to those originated in larger follicles.Study Design: A prospective study, undertaken in a university affiliated single center tertiary hospital. The study included 98 patients undergoing infertility treatments. On the day of ovum pickup (OPU) follicles were counted and measured. Aspiration of follicles larger and smaller than 10 mm was undertaken separately and the development of embryos originating from oocytes from these follicles was followed up using different wells for each embryo. There was no low limit of size for aspiration. Each oocyte retrieved was marked for its origin and numbered for further follow up. We recorded: Oocytes retrieved, maturation stage, fertilization rate, cleavage rate, morphokinetic parameters, embryo transfers, embryo freezing, oocyte freezing and biopsy rate for preimplantation genetic diagnosis (PGD). Quality was evaluated by the morphokinetic parameters of the embryos developed using time-lapse imaging technology. Day 3 KIDScore was calculated to all embryos.Results: Small follicles compared to large follicles displayed lower recovery rate (45% vs. 74%, P < 0.0001), fewer matured oocytes (37.5% vs. 61.7%, P < 0.0001), higher rates of GV oocytes (20.7% vs., 3.7%, P < 0.0001), and lower fertilization rate (43.7% vs. 63.3%, P < 0.0001. However, morphokinetic variables were similar between embryos that originated from either small or large follicles. Median KIDscores were identical for embryos from small or large follicle origin.Conclusions: Embryos originated from small follicles were not different than embryos from larger follicles, as assessed by morphokinetic parameters in time lapse system. In view of our findings, physicians should bear in mind that small follicle aspiration might yield good quality embryos. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the growth, health, and motor development of children born after preimplantation genetic diagnosis (PGD).Design: Observational cohort study and comparison of 5-year-old children born after PGD to similar aged children born after IVF/intracytoplasmic sperm injection (ICSI) and children from families with a genetic disorder born after natural conception (NC).Setting: University hospital.Patient(s): One hundred three children were included in the PGD group. The two control groups consisted of 90 children born after IVF/ICSI and 58 children born after NC.Intervention(s): PGD.Main Outcome Measure(s): We measured height, weight, body circumferences, body mass index, and blood pressure and performed a dysmorphological and neurological examination. We also collected data about the children's medical history, health care consultations, and motor milestones.Result(s): The mean height, weight, and body mass index were comparable for all groups. Six (5.8%) PGD, four (4.4%) IVF/ICSI, and five (8.6%) NC children had a major congenital abnormality. The incidence of acute and chronic illnesses was similar in all groups. Motor milestones were achieved on time, but the IVF/ICSI group had a slightly younger mean sitting age. None of the children had severe neurological problems.Conclusion(s): Five-year-old children born after PGD show normal growth, health, and motor development when compared with children born after IVF/ICSI and NC children from families with a genetic disorder.Trial Registration Number: NCT02149485. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the economical benefit of preimplantation genetic testing of aneuploidies (PGT-A) when applied in an extended culture and stringent elective single ET framework.Design: Theoretical cost-effectiveness study.Setting: Not applicable.Patients/animal(s): None.Intervention(s): Comparison of the cost-effectiveness between two IVF treatment strategies: serial transfer of all available blastocysts without genetic testing (first fresh transfer and subsequent frozen-thawed transfer); and systematic use of genetic testing (trophectoderm biopsy, freeze-all, and frozen-thawed transfers of euploid blastocysts). The costs considered for this analysis are based on regional public health system provider.Main Outcome Measure(s): Costs per live birth.Result(s): Cost-effectiveness profile of PGT-A improves with female age and number of available blastocysts. Sensitivity analyses varying the costs of ET, the costs of genetic analyses, the magnitude of the detrimental impact of PGT-A on live birth rate, and the crude live birth rates change to some extent the thresholds for effectiveness but generally confirm the notion that PGT-A can be economically advantageous in some specific subgroups.Conclusion(s): PGT-A can be cost-effective in specific clinical settings and population groups. Economic considerations deserve attention in the debate regarding the clinical utility of PGT-A. [ABSTRACT FROM AUTHOR]

Abstract Background Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive lysosomal storage disorder caused by GALNS gene mutation. The aim of our study is to detect pathogenic variants for patients suspected of MPS IVA and set the base for subsequent prenatal diagnosis and preimplantation genetic diagnosis. Methods In our study, 9 MPS IVA patients from south China families were investigated. Urine glycosaminoglycans (GAG S) screening was used as an initial method. For patients with abnormal result, all 14 exons and intron-exon junctions of the GALNS gene were sequenced after amplification from genomic DNA. The pathogenicity of novel mutations were analyzed with molecular genetics, bioinformatics and structure modeling in light of clinical manifestations and biochemical results. Results Among 12 mutations detected, direct sequencing found 3 novel mutations (c.686A>C, p.Y229S; c.1498G>T, p.G500C; c.278T>C, p.I93T). The pathogenicity of these novel mutations was illustrated by correlating clinical symptoms with pedigree analysis and bioinformatics analysis. Conclusion The detection and variant analysis are essential for accurate diagnosis of MPS IVA patients. Our results enrich GALNS gene mutation spectrum of Chinese population. This information has important clinical value for molecular diagnosis and genetic counseling of patients with this disease. Highlights • We investigated eight pedigrees with rare autosomal recessive Mucopolysaccharidosis type IVA in south China. • Detailed genotypic and phenotypic correlation study of 8 families of mucopolysaccharidosis type IVA was performed. • Revealed three novel heterozygous mutations (c.686A>C, p.Y229S, c.1498G>T, p.G500C and c.278T>C, p.I93T) of GALNS gene. • Mutations were predicted to be pathogenic by clinical diagnosis, genetics analysis and bioinformatics. • It has an important role in future genetic counseling and aristogenesis. [ABSTRACT FROM AUTHOR]

Abstract In cattle breeding, the development of genomic selection strategies based on single nucleotide polymorphism (SNP) interrogation has led to improved rates of genetic gain. Additionally, the application of genomic selection to in-vitro produced (IVP) embryos is expected to bring further benefits thanks to the ability to test a greater number of individuals before establishing a pregnancy and to ensure only carriers of desirable traits are born. However, aneuploidy, a leading cause of developmental arrest, is known to be common in IVP embryos. Karyomapping is a comprehensive screening test based on SNP typing that can be used for simultaneous genomic selection and aneuploidy detection, offering the potential to maximize pregnancy rates. Moreover, Karyomapping can be used to characterize the frequency and parental origin of aneuploidy in bovine IVP embryos, which have remained underexplored to date. Here, we report the use of Karyomapping to characterize the frequency and parental origin of aneuploidy in IVP bovine embryos in order to establish an estimate of total aneuploidy rates in each parental germline. We report an estimate of genome wide recombination rate in cattle and demonstrate, for the first time, a proof of principle for the application of Karyomapping to cattle breeding, with the birth of five calves after screening. This combined genomic selection and aneuploidy screening approach was highly reliable, with calves showing 98% concordance with their respective embryo biopsies for SNP typing and 100% concordance with their respective biopsies for aneuploidy screening. This approach has the potential to simultaneously improve pregnancy rates following embryo transfer and the rate of genetic gain in cattle breeding, and is applicable to basic research to investigate meiosis and aneuploidy. Highlights • The first application of Karyomapping to cattle breeding leading to 5 liveborns. • Karyomapping applicable for genomic selection, chromosome screening, basic research. • We describe the frequency of meiotic recombination and meiotic errors in cattle. • We assess the concordance between SNP calls from blastocyst biopsies and liveborns. [ABSTRACT FROM AUTHOR]