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Effect of parental origin and predictors for obtaining a euploid embryo in balanced translocation carriers

  • Jing Tong
    Affiliations
    Center for Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200135, China

    Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
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  • Yichao Niu
    Affiliations
    Center for Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200135, China

    Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
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  • Anran Wan
    Affiliations
    Center for Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200135, China

    Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
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  • Ting Zhang
    Correspondence
    Corresponding author.
    Affiliations
    Center for Reproductive Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200135, China

    Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China
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Open AccessPublished:September 21, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.09.007

      Abstract

      Research question

      What is the effect of parental origin of translocation and predictors for obtaining a euploid embryo in preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) for balanced translocation carriers?

      Design

      A total of 179 PGT-SR cycles and 614 blastocysts from 123 couples carrying a balanced translocation were retrospectively analysed. Next-generation sequencing (NGS) was performed after trophectoderm biopsy.

      Results

      There were no differences in ovarian stimulation parameters or PGT-SR outcomes regarding the number of oocytes retrieved (11.95 ± 5.71 versus 11.82 ± 6.26), blastulation rate (0.42 ± 0.27 versus 0.45 ± 0.28), biopsy cancellation rate (11.7% versus 12.9%), the number of blastocysts for biopsy (3.70 ± 2.58 versus 4.04 ± 3.51), or the component of euploid embryos (23.80% versus 25.42%), aneuploid embryos (58.10% versus 57.52%) and mosaic embryos (18.10% versus 17.06%) between female carriers and male partner carriers. In a multivariate logistic regression model, the number of blastocysts for biopsy (adjusted odds ratio 1.752; 95% confidence interval 1.359–2.259; P < 0.001) was significantly associated with the chance of obtaining at least one euploid embryo. Receiver operating characteristic analysis with a threshold of 3.5 was conducted to calculate the number of blastocysts required for biopsy to obtain at least one euploid embryo.

      Conclusions

      The parental origin of translocation does not significantly affect the PGT-SR outcomes for young balanced translocation carriers. At least 3.5 blastocysts are required to obtain one euploid embryo. Couples should be informed that the probability of obtaining one euploid embryo is low when fewer than 4 blastocysts are obtained in one PGT cycle.

      KEYWORDS

      Introduction

      Balanced translocation is a relatively common chromosome structural rearrangement, which occurs when the terminal segments exchange between different chromosomes (
      • Lledó B.
      • Ortiz J.A.
      • Morales R.
      • Ten J.
      • de la Fuente P.E.
      • García-Ochoa C.G.
      • Bernabeu R.
      The paternal effect of chromosome translocation carriers observed from meiotic segregation in embryos.
      ). There are two different types of balanced translocations in humans. The first is Robertsonian translocations, which involve centric fusion of two acrocentric chromosomes including chromosomes 13, 14, 15, 21 and 22, with an incidence of about 1 in 1000 people. The second type, balanced reciprocal translocations, involve material exchange between any two different chromosomes, with an incidence of about 1 in 700–750 people (
      • Van Dyke D.L.
      • Weiss L.
      • Roberson J.R.
      • Babu V.R.
      The frequency and mutation rate of balanced autosomal rearrangements in man estimated from prenatal genetic studies for advanced maternal age.
      ).
      Balanced translocation carriers exhibit normal phenotypes with no overall gain or loss of genetic material abnormalities; however, they still encounter fertility problems such as infertility, recurrent spontaneous abortion or birth of affected children due to the chromosomally abnormal embryos because the carriers have produced unbalanced gametes (
      • Fiorentino F.
      • Spizzichino L.
      • Bono S.
      • Biricik A.
      • Kokkali G.
      • Rienzi L.
      • Ubaldi F.M.
      • Iammarrone E.
      • Gordon A.
      • Pantos K.
      PGD for reciprocal and Robertsonian translocations using array comparative genomic hybridization.
      ). In the meiosis I process, the translocated chromosomes and their normal homologues will form a quadrivalent structure that are segregated into five theoretical modes, including alternate, adjacent-1, adjacent-2, 3:1 and 4:0 (
      • Scriven P.N.
      • Handyside A.H.
      • Ogilvie C.M.
      Chromosome translocations: segregation modes and strategies for preimplantation genetic diagnosis.
      ). Where recombination occurs, only one type of normal and one type of balanced gametes are produced, while the others are chromosomally unbalanced. The frequency of unbalanced gametes differs greatly, ranging from 19.0% to 91.0% depending on the presence of acrocentric chromosomes (
      • Lim C.K.
      • Cho J.W.
      • Song I.O.
      • Kang I.S.
      • Yoon Y.D.
      • Jun J.H.
      Estimation of chromosomal imbalances in preimplantation embryos from preimplantation genetic diagnosis cycles of reciprocal translocations with or without acrocentric chromosomes.
      ), the breakpoint position (
      • Ko D.S.
      • Cho J.W.
      • Park S.Y.
      • Kim J.Y.
      • Koong M.K.
      • Song I.O.
      • Kang I.S.
      • Lim C.K.
      Clinical outcomes of preimplantation genetic diagnosis (PGD) and analysis of meiotic segregation modes in reciprocal translocation carriers.
      ;
      • Ye Y.
      • Qian Y.
      • Xu C.
      • Jin F.
      Meiotic segregation analysis of embryos from reciprocal translocation carriers in PGD cycles.
      ) and even the carrier sex (
      • Harper J.C.
      • Wilton L.
      • Traeger-Synodinos J.
      • Goossens V.
      • Moutou C.
      • SenGupta S.B.
      • Budak T.P.
      • Renwick P.
      • de Rycke M.
      • Geraedts J.P.M.
      • Harton G.
      The ESHRE PGD Consortium: 10 years of data collection.
      ;
      • Lledó B.
      • Ortiz J.A.
      • Morales R.
      • Ten J.
      • de la Fuente P.E.
      • García-Ochoa C.G.
      • Bernabeu R.
      The paternal effect of chromosome translocation carriers observed from meiotic segregation in embryos.
      ).
      Preimplantation genetic testing (PGT) for chromosomal structural rearrangements (PGT-SR) refers to genetic testing of an embryo biopsy in balanced translocation carriers to select the normal/balanced embryos for transfer. This technology can effectively reduce the abortion rate, avoid the selective termination of affected pregnancies and improve the live birth rates. Nonetheless, according to a report from the European Society of Human Reproduction and Embryology (ESHRE) consortium, only 26% of successfully diagnosed embryos are suitable for transfer (
      • Harper J.C.
      • Wilton L.
      • Traeger-Synodinos J.
      • Goossens V.
      • Moutou C.
      • SenGupta S.B.
      • Budak T.P.
      • Renwick P.
      • de Rycke M.
      • Geraedts J.P.M.
      • Harton G.
      The ESHRE PGD Consortium: 10 years of data collection.
      ). In other words, not every couple where one partner has balanced translocation can obtain one, or sufficient, blastocysts for biopsy to obtain at least one euploid embryo. When taking into account the PGT-SR cost for a family in developing countries, it is worth providing parameters in genetic counselling that can predict the PGT-SR outcomes for balanced translocation carriers.
      This study retrospectively analysed PGT-SR outcomes with next-generation sequencing (NGS) technology, so as to investigate whether the parental origin of translocation is an influencing factor in obtaining euploid embryos and what the predictive factors are for euploid embryos in the balanced translocation carriers.

      Materials and methods

       Participants

      From January 2020 to August 2020, a total of 123 couples seeking PGT-SR counselling for a balanced translocation carried by either the male or female partner at the study centre were recruited (Figure 1). Written informed consent (which described the limitations and advantages of PGT-SR) was provided by each participant before the start of ovarian stimulation. Data collection for this retrospective study was approved by the Renji Hospital Ethics Committee, Shanghai Jiaotong University School of Medicine (no: 20200834, 17 August 2020).
      Figure 1
      Figure 1Study design. PGT-SR = preimplantation genetic testing for chromosomal structural rearrangements; ROC = receiver operating characteristic.
      Basic characteristics of all participants were collected, including age and body mass index (BMI). Standard chromosomal analyses on the cultured peripheral lymphocytes were carried out for all participants using the standard G-banding procedures. For females, the baseline (on Day 2–4 of a previous menstrual cycle) serum contents of FSH, LH, oestradiol, testosterone, prolactin (PRL), anti-Müllerian hormone (AMH) and thyroid-stimulating hormone (TSH) were measured. For males, semen samples were generated by masturbation and ejaculated into clean, wide-mouthed plastic containers after at least 48 h of abstinence; semen samples were then evaluated by standard procedures, according to the World Health Organization (WHO) criteria for ejaculate volume, sperm concentration and progressive motility.

       Ovarian stimulation

      The ovarian stimulation regimens using gonadotrophin-releasing hormone (GnRH) analogues and gonadotrophins were selected based on different clinical factors such as age, weight, basal hormonal concentrations, AMH concentrations, ovarian volume and previous ovarian stimulation, if available. Follicle development was monitored by ultrasound scans at intervals of 1–3 days until the stimulation day. Simultaneously, the concentrations of serum oestradiol, FSH, LH and progesterone were detected. When the lead follicles reached a mean diameter of 18–20 mm with a serum oestradiol concentration of 200–300 pg/ml per mature follicle (greater than 14 mm), the final oocyte maturation was stimulated using GnRH agonist at a dose of 0.2 mg once and/or human chorionic gonadotrophin (HCG) at a dose of 2000–8000 IU. Ultrasound-guided oocyte collection was performed 33–36 h later.

       NGS-based PGT-SR procedure

      Intracytoplasmic sperm injection (ICSI) was applied in all the metaphase II (MII) oocytes. Fertilization was confirmed by the presence of two pronuclei (2PN) at 17–20 h later. Additionally, the embryo cleavage was evaluated at 41–44 h (Day 2) and 65–68 h (Day 3) after ICSI, respectively. All embryos were cultured to the blastocyst stage under assisted hatching, and trophectoderm (TE) biopsy was conducted on Day 5 or 6. The blastulation rate was calculated by dividing the total number of blastocysts in a cycle by the total number of fertilized oocytes.
      NGS allows direct reading of the sequenced DNA fragments and their quantification based on the sequence read numbers. In accordance with the Illumina NGS platform protocol, NGS involved five steps: (i) sample processing related to the handling of TE cells, cell lysis, barcoding, adapter ligation, amplification, library preparation, flow cell loading and generation of sequence reads; (ii) initial quality analysis; (iii) library preparation; (iv) sequencing where DNA sequence generation by NGS platforms was almost entirely automated; (v) data analysis in which raw data were further processed by computational and bioinformatic analyses using a variety of algorithms for mapping and aligning the short sequence reads to a linear reference human genome sequence. In addition, embryos with aneuploid percentages between 20% and 80% are classified as mosaicism, aneuploid percentages below 20% are classified as euploidy, and over 80% as aneuploidy.

       Statistical analysis

      Continuous data are expressed as mean ± SD, and categorical variables presented as absolute and percentage frequencies. Differences in basic characteristics, ovarian stimulation and PGT-SR outcomes between the two groups were compared by two-sample t-test or chi-squared test, as appropriate.
      The chances of obtaining at least one euploid embryo were explored using the bivariate logistic regression models based on the basic characteristics and ovarian stimulation factors. Subsequently, multivariate logistic regression analysis was conducted using a model that incorporated all significant parameters identified from bivariate analysis. The number of biopsied embryos was confirmed to be significantly correlated with the chances of obtaining at least one euploid embryo (P < 0.001). Thereafter, the receiver operating characteristic (ROC) curves were plotted and Youden index analysis performed to determine a threshold that maximized the chance of obtaining one euploid embryo according to the number of biopsied embryos for balanced translocation, balanced reciprocal translocation and Robertsonian translocation carriers, respectively.
      All data were analysed using SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY, USA). P-values <0.05 indicated a statistically significant difference.

      Results

       Population characteristics

      This study included 123 couples who underwent 179 PGT-SR cycles, and altogether 614 blastocysts were formed and biopsied in 157 cycles. Baseline characteristics of patients are reported in Table 1. The female carrier group was not significantly different from the male carrier group in terms of male or female age, male or female BMI at the time of the cycle, basal FSH, LH, oestradiol, PRL and testosterone concentrations, TSH concentration, semen volume or sperm morphology. In addition, compared with the female carrier group, the male carrier group had significantly decreased serum AMH concentrations (3.37 ± 2.16 ng/ml versus 4.49 ± 3.20 ng/ml, P = 0.036), sperm count (48.67 ± 42.47 million/ml versus 66.09 ± 46.32 million/ml, P = 0.039), total motility (31.83 ± 17.08% versus 42.90 ± 12.23%, P < 0.001), progressive spermatozoa (26.62 ± 15.14% versus 35.98 ± 10.56%, P < 0.001) and slow progressive spermatozoa (6.88 ± 3.56% versus 8.77 ± 3.67%, P = 0.008).
      Table 1Study population characteristics
      ParameterFemale carriers (n = 62)Male carriers (n = 61)P-value
      Female age, years30.23 ± 3.5530.57 ± 3.970.609
      Female BMI, kg/m224.66 ± 17.2021.83 ± 2.930.200
      AMH concentration, ng/ml4.49 ± 3.203.37 ± 2.160.036
      Basal FSH concentration, IU/l6.69 ± 2.876.45 ± 3.260.694
      Basal LH concentration, IU/l5.38 ± 3.255.29 ± 3.910.898
      Basal oestradiol concentration, pg/ml39.70 ± 19.8545.81 ± 35.960.285
      Basal PRL concentration, ng/ml15.85 ± 14.5116.96 ± 16.200.430
      Basal testosterone concentration, nmol/l0.62 ± 0.610.57 ± 0.510.688
      TSH concentration, mIU/l2.03 ± 1.072.12 ± 1.490.716
      Male age, years32.08 ± 4.1232.16 ± 5.360.923
      Male BMI, kg/m224.82 ± 3.3724.47 ± 3.550.576
      Semen volume, ml2.67 ± 1.183.11 ± 3.050.303
      Sperm count, million/ml66.09 ± 46.3248.67 ± 42.470.039
      Total motility, %42.90 ± 12.2331.83 ± 17.08<0.001
      Progressive spermatozoa, %35.98 ± 10.5626.62 ± 15.14<0.001
      Slow progressive spermatozoa, %8.77 ± 3.676.88 ± 3.560.008
      Sperm morphology, %3.50 ± 1.382.20 ± 0.840.345
      Data are presented as mean ± SD or n (%).
      AMH = anti-Müllerian hormone; BMI = body mass index; PRL = prolactin; TSH = thyroid-stimulating hormone.

       Ovarian stimulation and PGT-SR outcomes

      As shown in Table 2, the stimulation characteristics were examined, which revealed that the initial FSH dose (132.38 ± 80.23 IU versus 139.36 ± 75.59 IU), total FSH dose (1093.37 ± 841.19 IU versus 1085.61 ± 700.29 IU), duration of stimulation (8.43 ± 1.32 days versus 8.30 ± 1.40 days), serum oestradiol concentration on the stimulation day (2744.28 ± 1743.06 pg/ml versus 2709.34 ± 1625.29 pg/ml), LH concentration on the stimulation day (3.52 ± 2.53 IU/l versus 3.73 ± 2.81 IU/l) and progesterone concentration on the stimulation day (0.63 ± 0.35 ng/l versus 0.70 ± 0.44 ng/l) were not significantly different between female carriers and partners of male carriers. With regard to the PGT-SR outcomes, there were no statistically significant differences in the number of oocytes retrieved (11.95 ± 5.71 versus 11.82 ± 6.26), the number of MII oocytes (10.12 ± 4.92 versus 10.34 ± 5.19), the number of oocytes fertilized (2PN) (8.08 ± 4.22 versus 8.03 ± 4.15), the number of fertilized oocytes that cleaved (8.01 ± 4.17 versus 7.89 ± 4.11), blastulation rate (0.42 ± 0.27 versus 0.45 ± 0.28), biopsy cancellation rate (11.7% versus 12.9%), or the number of blastocysts for biopsy (3.70 ± 2.58 versus 4.04 ± 3.51), as well as the component of euploid embryos (23.80% versus 25.42%), aneuploid embryos (58.10% versus 57.52%) and mosaic embryos (18.10% versus 17.06%) between female carriers and partners of male carriers.
      Table 2Ovarian stimulation and PGT-SR outcomes according to female or male carriers
      ParameterFemale carriersPartners of male carriersP-value
      No. of cycles9485N/A
      Initial FSH dose, IU132.38 ± 80.23139.36 ± 75.590.577
      Total FSH dose, IU1093.37 ± 841.191085.61 ± 700.290.950
      Duration of stimulation, days8.43 ± 1.328.30 ± 1.400.531
      Oestradiol concentration on the stimulation day, pg/ml2744.28 ± 1743.062709.34 ± 1625.290.898
      LH concentration on the stimulation day, IU/l3.52 ± 2.533.73 ± 2.810.616
      Progesterone concentration on the stimulation day, ng/l0.63 ± 0.350.70 ± 0.440.290
      No. of oocytes retrieved11.95 ± 5.7111.82 ± 6.260.894
      No. of MII oocytes10.12 ± 4.9210.34 ± 5.190.788
      No. of oocytes fertilized (2PN)8.08 ± 4.228.03 ± 4.150.932
      No. of fertilized oocytes that cleaved8.01 ± 4.177.89 ± 4.110.855
      Blastulation rate0.42 ± 0.270.45 ± 0.280.536
      Biopsy cancellation rate, % (n)11.7 (11)12.9 (11)0.801
      No. of blastocysts for biopsy3.70 ± 2.584.04 ± 3.510.485
      PGT-SR results0.876
      Euploidy, % (n)23.80 (75)25.42 (76)
      Aneuploidy, % (n)58.10 (183)57.52 (172)
      Mosaicism, % (n)18.10 (57)17.06 (51)
      Data are presented as mean ± SD or n (%).
      2PN = two-pronuclear; MII = metaphase II; PGT-SR = preimplantation genetic testing for chromosomal structural rearrangements.

       Parameters affecting the chances of obtaining at least one euploid embryo

      Among the 179 PGT-SR cycles of balanced translocations, 91 (57.96%) obtained at least one euploid embryo (Figure 1). Using the bivariate logistic regression models and then multivariate logistic regression analysis, it was found that the number of blastocysts for biopsy (crude OR 1.566; 95% confidence interval [CI] 1.293–1.897; P < 0.001), female age (crude OR 0.849; 95% CI 0.769–0.938; P = 0.001), male age (crude OR 0.861; 95% CI 0.790–0.938; P = 0.001), the number of MII oocytes (crude OR 1.074; 95% CI 1.004–1.148; P = 0.038), the number of oocytes fertilized (2PN) (crude OR 1.101; 95% CI 1.013–1.195; P = 0.023) and the number of fertilized oocytes that cleaved (crude OR 1.106; 95% CI 1.016–1.203; P = 0.02) were significantly associated with the chances of obtaining at least one euploid embryo (Table 3). Additionally, the number of consecutive cycles per patient as a variable was not significantly associated with the opportunity to obtain a euploid embryo in the bivariate logistic regression model (crude OR 0.906; 95% CI 0.602–1.364; P = 0.637). Thus, this variable was not included in the multivariate logistic regression model. The sperm parameters were not significantly associated with the chances of obtaining a euploid embryo; there was no significant difference in sperm parameters in balanced translocation carrier couples who obtained at least one euploid embryo, compared with those who failed to obtain a euploid embryo (Supplementary Table 1).
      Table 3Multivariate model for predictors of obtaining a euploid embryo
      VariableObtained at least one euploid embryo
      Crude OR (95% CI)P-valueAdjusted OR (95% CI)P-value
      No. of blastocysts for biopsy1.566 (1.293–1.897)<0.0011.752 (1.359–2.259)<0.001
      Female age0.849 (0.769–0.938)0.0010.949 (0.803–1.122)0.541
      Male age0.861 (0.790–0.938)0.0010.879 (0.763–1.012)0.073
      No. of MII oocytes1.074 (1.004–1.148)0.0380.956 (0.797–1.147)0.628
      No. of oocytes fertilized (2PN)1.101 (1.013–1.195)0.0230.830 (0.260–2.656)0.754
      No. of fertilized oocytes that cleaved1.106 (1.016–1.203)0.0201.118 (0.344–3.633)0.853
      2PN = two-pronuclear; CI = confidence interval; MII = metaphase II; OR = odds ratio.
      As revealed by the multivariate logistic regression model that incorporated all the significant parameters, only the number of blastocysts for biopsy (adjusted OR 1.752; 95% CI 1.359–2.259; P < 0.001) was still significantly associated with the chances of obtaining at least one euploid embryo (Table 3).
      Table 4 and Figure 2 present the area under the curve (AUC), the estimated sensitivity and specificity for the threshold used for the number of blastocysts for biopsy as a predictor for obtaining a euploid embryo in balanced translocation, balanced reciprocal translocation and Robertsonian translocations carriers. The AUC values calculated for the number of blastocysts for biopsy in both balanced translocation and balanced reciprocal translocation groups were above 0.8, whereas that in the Robertsonian translocation group was less than 0.7. For the balanced translocation and the balanced reciprocal translocation groups, the threshold of 3.5 blastocysts for biopsy resulted in an estimated sensitivity of 59.8 and 63.8, with a specificity of 82.0% and 84.0%, respectively. As for the Robertsonian translocation group, this threshold decreased to 1.5 blastocysts for biopsy, which led to estimated sensitivity of 83.3% and specificity of 40.0%.
      Table 4Received operator characteristic curve results relating to prediction of obtaining an euploid embryo
      AUC95% CIP-valueCut-off levelSensitivity (%)Specificity (%)
      No. of blastocysts for biopsyReciprocal translocation0.8030.741–0.865<0.0013.559.882.0
      Balanced translocation0.8120.745–0.879<0.0013.563.884.0
      Robertsonian translocations (ROBT)0.6000.352–0.8480.4291.583.340.0
      Figure 2
      Figure 2Receiver operating characteristic curve showing the number of blastocysts required for biopsy as a predictor for obtaining a euploid embryo in balanced translocation (solid blue line), balanced reciprocal translocation (solid red line) and Robertsonian translocation (dashed red line) carriers.

      Discussion

      This analysis of 179 PGT-SR cycles and 614 blastocysts from 123 couples carrying a balanced translocation demonstrated that the presence of translocation seemed not to affect the ovarian response to ovarian stimulation in the female carriers; besides, the parental origin of balanced translocation was not significantly associated with PGT-SR outcomes. The number of blastocysts for biopsy predicted the chances of obtaining at least one normal/balanced (euploid) embryo for balanced translocation carriers. To be specific, the minimum number of blastocysts required to obtain at least one normal/balanced embryo for balanced translocation and balanced reciprocal translocation carriers was 3.5, while that for Robertsonian translocation carriers was 1.5.
      In previous studies, female translocation carriers were assumed to be associated with gonadal dysfunction or ovarian function impairment, particularly when the breakpoints fall within critical regions involved in maintaining the ovarian function (
      • Burton K.A.
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      Autosomal translocation associated with premature ovarian failure.
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      • Bharucha B.A.
      Ovarian dysgenesis with balanced autosomal translocation.
      ). Some sporadic cases carrying balanced autosomal Robertsonian and reciprocal translocations complicated with premature ovarian failure have been reported (
      • Kawano Y.
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      • Matsui N.
      • Miyakawa I.
      Premature ovarian failure associated with a Robertsonian translocation.
      ;
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      • Pal L.
      Diminished ovarian reserve in a woman with a balanced 13;21 translocation.
      ;
      • Tosun S.A.
      • Tosun A.
      • Ozkaya E.
      Premature ovarian failure in a patient with Robertsonian translocation rob (14;15): is it only a coincidence?.
      ). Theoretically, it is widely accepted that high doses of gonadotrophins are used for female translocation carriers in PGT-SR cycles, so as to obtain high numbers of oocytes. However, studies into the ovarian function and ovarian stimulation response in female translocation carriers have produced inconclusive results. Based on the current results, comparing female translocation carriers and partners of male translocation carriers, no difference was observed in the couple's age or female basal FSH concentration, except that a significantly higher serum AMH concentration was found in female carriers. No differences were observed in ovarian stimulation parameters, such as the initial dose of FSH, the total dose of FSH, duration of stimulation, the number of oocytes retrieved or the number of MII oocytes, suggesting that there was no decreased ovarian response in female carriers. The presence of translocation appears not to affect the ovarian response to ovarian stimulation; therefore, standard doses of gonadotrophins will be sufficient in these cases, which agrees with results reported by Dechanet et al. (2001),
      • Keymolen K.
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      • Verpoest W.
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      A proposal for reproductive counselling in carriers of Robertsonian translocations: 10 years of experience with preimplantation genetic diagnosis.
      and
      • Goossens V.
      • Harton G.
      • Moutou C.
      • Traeger-Synodinos J.
      • van Rij M.
      • Harper J.C.
      ESHRE PGD Consortium data collection IX: cycles from January to December 2006 with pregnancy follow-up to October 2007.
      .
      With regard to male translocation carriers, altered semen parameters are commonly found, probably due to meiotic disturbances that cause cell cycle arrest and spermatogenesis impairment (
      • Rao K.L.
      • Babu K.A.
      • Kanakavalli M.K.
      • Padmalatha V.V.
      • Deenadayal M.
      • Singh L.
      Prevalence of chromosome defects in azoospermic and oligoastheno-teratozoospermic South Indian infertile men attending an infertility clinic.
      ;
      • Vozdova M.
      • Oracova E.
      • Kasikova K.
      • Prinosilova P.
      • Rybar R.
      • Horinova V.
      • Gaillyova R.
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      Balanced chromosomal translocations in men: relationships among semen parameters, chromatin integrity, sperm meiotic segregation and aneuploidy.
      ). The current study also detected the poor semen parameters, including sperm count, total motility, progressive spermatozoa and slow progressive spermatozoa, in male translocation carriers compared with partners of female translocation carriers. However, there was no significant difference in sperm parameters including sperm volume, sperm count, total motility, progressive spermatozoa and slow progressive spermatozoa in balanced translocation carrier couples who obtained at least one euploid embryo, compared with those who failed to obtain a euploid embryo. This can be attributed to the ICSI technology that is applied conventionally in PGT cycles, which may facilitate the selection of spermatozoa with normal/balanced chromosome contents and improve the euploid embryo rate in male carriers (
      • Lei C.
      • Zhang S.
      • Zhu S.
      • Wu J.
      • Xiao M.
      • Zhou J.
      • Fu J.
      • Sun Y.
      • Xu C.
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      Conventional ICSI improves the euploid embryo rate in male reciprocal translocation carriers.
      ).
      It was reported differences in the frequency and localization of crossing over that determined the meiotic configurations and affected the proportion of segregation patterns between males and females, and a higher proportion of products was derived from adjacent-1 segregation in males than in females (27.6% versus 23.8%) (
      • Lledó B.
      • Ortiz J.A.
      • Morales R.
      • Ten J.
      • de la Fuente P.E.
      • García-Ochoa C.G.
      • Bernabeu R.
      The paternal effect of chromosome translocation carriers observed from meiotic segregation in embryos.
      ). From a practical point of view, more attention should be paid to the proportion of normal/balanced embryos with respect to the parental origin of balanced translocation. There are thought to be only three studies carried out in this area. While data from the current study clearly demonstrate that the parental origin of balanced translocation is not significantly associated with PGT-SR outcomes, which is consistent with results obtained by
      • Lledó B.
      • Ortiz J.A.
      • Morales R.
      • Ten J.
      • de la Fuente P.E.
      • García-Ochoa C.G.
      • Bernabeu R.
      The paternal effect of chromosome translocation carriers observed from meiotic segregation in embryos.
      and
      • Ogilvie C.M.
      • Scriven P.N.
      Meiotic outcomes in reciprocal translocation carriers ascertained in 3-day human embryos.
      , this is in contrast to the third study (
      • Mayeur A.
      • Ahdad N.
      • Hesters L.
      • Grynberg M.
      • Romana S.
      • Sonigo C.
      • Frydman N.
      Does the prognosis after PGT for structural rearrangement differ between female and male translocation carriers?.
      ). The overall incidence of normal/balanced (euploid) embryos was comparable between female carriers and the partners of male carriers (23.80% and 25.42%, respectively), which was lower than those reported in two earlier studies (
      • Lledó B.
      • Ortiz J.A.
      • Morales R.
      • Ten J.
      • de la Fuente P.E.
      • García-Ochoa C.G.
      • Bernabeu R.
      The paternal effect of chromosome translocation carriers observed from meiotic segregation in embryos.
      ;
      • Ogilvie C.M.
      • Scriven P.N.
      Meiotic outcomes in reciprocal translocation carriers ascertained in 3-day human embryos.
      ). These discrepancies are probably due to the genome-wide analysis technology adopted in the current study. To be specific, NGS, an up-to-date technology, has a higher dynamic range than array comparative genomic hybridization (CGH) or fluorescence in-situ hybridization (FISH). Using the NGS approach, segmental mosaicism and small chromosome deletions or duplications (typically >10 Mb) can be detected. Moreover, NGS enables sequencing to screen the structural variations at a cost comparable to that of microarrays in standard clinical practice (
      • Talkowski M.E.
      • Ernst C.
      • Heilbut A.
      • Chiang C.
      • Hanscom C.
      • Lindgren A.
      • Kirby A.
      • Liu S.
      • Muddukrishna B.
      • Ohsumi T.K.
      • Shen Y.
      • Borowsky M.
      • Daly M.J.
      • Morton C.C.
      • Gusella J.F.
      Next-generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research.
      ).
      It is worth noting that this study showed that the number of biopsy blastocysts was correlated with the chances of obtaining at least one euploid embryo. The results demonstrated that one normal/balanced (euploid) embryo was likely to be obtained from 3.5 blastocysts in balanced translocation carriers and balanced reciprocal translocation carriers, but from 1.5 blastocysts in Robertsonian translocation carriers. This indicated that the chances of obtaining a euploid embryo increased by two-fold in Robertsonian translocation carriers relative to balanced reciprocal translocation carriers. Indeed, a majority of Robertsonian translocation carriers are able to have their own offspring through natural conception, without any awareness of their translocations. As for couples carrying balanced translocations, the current findings suggest that a certain number of biopsy blastocysts might be used to predict the chances of obtaining a euploid embryo. In the genetic counselling before the initiation of PGT-SR, couples should be informed that the probability of obtaining one euploid embryo is low if fewer than 4 blastocysts are biopsied.
      However, the interpretation of the current results should be restricted to young female partners around 30 years old, because much evidence shows that maternal age is the main cause of embryonic aneuploidies. The no euploid embryo rate was lowest (2–6%) in women aged 26 to 37, was 33% at age 42, and was 53% at age 44 (
      • Franasiak J.M.
      • Forman E.J.
      • Hong K.H.
      • Werner M.D.
      • Upham K.M.
      • Treff N.R.
      • Scott R.T.
      The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.
      ;
      • Gruhn J.R.
      • Zielinska A.P.
      • Shukla V.
      • Blanshard R.
      • Capalbo A.
      • Cimadomo D.
      • Nikiforov D.
      • Chan A.C.H.
      • Newnham L.J.
      • Vogel I.
      • Scarica C.
      • Krapchev M.
      • Taylor D.
      • Kristensen S.G.
      • Cheng J.
      • Ernst E.
      • Bjørn A.M.B.
      • Colmorn L.B.
      • Blayney M.
      • Elder K.
      • Liss J.
      • Hartshorne G.
      • Grøndahl M.L.
      • Rienzi L.
      • Ubaldi F.
      • McCoy R.
      • Lukaszuk K.
      • Andersen C.Y.
      • Schuh M.
      • Hoffmann E.R.
      Chromosome errors in human eggs shape natural fertility over reproductive life span.
      ). However, the incidence of aneuploidy in spermatozoa is independent of paternal age (
      • Lu S.
      • Zong C.
      • Fan W.
      • Yang M.
      • Li J.
      • Chapman A.R.
      • Zhu P.
      • Hu X.
      • Xu L.
      • Yan L.
      • Bai F.
      • Qiao J.
      • Tang F.
      • Li R.
      • Xie X.S.
      Probing meiotic recombination and aneuploidy of single sperm cells by whole-genome sequencing.
      ;
      • Wang J.
      • Fan H.C.
      • Behr B.
      • Quake S.R.
      Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm.
      ). The situation is expected to be more complex when the balanced translocation carriers are of advanced age, especially for female carriers. The aneuploidy information for balanced translocation carriers of advanced age in this study is shown in Supplementary Table 2. Only two aneuploid blastocysts (2/24, 8.33%) obtained from 10 females of advanced age were found involving non-translocation chromosomes. According to the current limited data, the majority of aneuploid blastocysts in balanced translocation carriers of advanced age were still involved with parental translocation chromosomes. The reduced chances of aged women obtaining blastocysts for biopsy may hide the true effect of advanced maternal age combined with translocation on embryo aneuploidy, which still remains unknown and is yet to be proved.
      Moreover, the embryo mosaicism rate revealed by this study was around 17%, which appears to be a little higher than previously reported in couples with normal karyotype (
      • Tong J.
      • Niu Y.
      • Wan A.
      • Zhang T.
      Next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) of trophectoderm biopsy for recurrent implantation failure (RIF) patients: a retrospective study.
      ); this is consistent with a study by
      • Emiliani S.
      • Gonzalez-Merino E.
      • van den Bergh M.
      • Abramowicz M.
      • Englert Y.
      Higher degree of chromosome mosaicism in preimplantation embryos from carriers of Robertsonian translocation t(13;14) in comparison with embryos from karyotypically normal IVF patients.
      , which demonstrated a higher degree of chromosome mosaicism from Robertsonian translocation carriers in comparison with karyotypically normal patients. But the exact origin and nature of this phenomenon, including non-disjunction combined with anaphase lag, mitotic errors due to lack of cell checkpoint controls or translocation-specific factors, are still subject to study. Because healthy live births after mosaic aneuploidy blastocyst transfer were reported in 2015 for the first time, the management of mosaic embryos in clinics attract a lot of attention, especially when there is no euploid embryo for transfer. However, the exact risk to fetuses after transfer of mosaic blastocysts is still unknown and the option should be provided only after patient counselling with an emphasis on prenatal testing (particularly amniocentesis) (
      Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive Medicine
      Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion.
      ). Similar to other retrospective studies, certain limitations should be noted in the present study, the most important being the limited cases of Robertsonian translocation carriers recruited. Although the ROC analysis results were consistent with other studies (
      • Wang Y.
      • Ding C.
      • Wang J.
      • Zeng Y.
      • Zhou W.
      • Li R.
      • Zhou C.
      • Deng M.-F.
      • Xu Y.
      Number of blastocysts biopsied as a predictive indicator to obtain at least one normal/balanced embryo following preimplantation genetic diagnosis with single nucleotide polymorphism microarray in translocation cases.
      ;
      • Xiong B.
      • Tan K.
      • Tan Y.Q.
      • Gong F.
      • Zhang S.P.
      • Lu C.F.
      • Luo K.L.
      • Lu G.X.
      • Lin G.
      Using SNP array to identify aneuploidy and segmental imbalance in translocation carriers.
      ), the AUC value calculated for the number of blastocysts for biopsy in the Robertsonian translocation group was less than 0.7, indicating the sub-optimal performance. Another limitation was that balanced embryos were not distinguished from the structurally normal embryos by testing the single gene defects using the polymorphic short tandem repeat (STR) markers, because the extra economic burden of this is inappropriate for most families in a developing country.
      In conclusion, this single-centre, retrospective, observational study analysed 179 PGT-SR cycles and 614 blastocysts from 123 couples carrying a balanced translocation. The data constitute a new contribution to research into the effect of parental origin of balanced translocation and predictors for PGT-SR outcomes in balanced translocation carriers, a topic that has seldomly been investigated previously. The results confirm that the presence of translocations appears not to affect the female's ovarian response to ovarian stimulation, and standard doses of gonadotrophins would be sufficient in these cases. Also, the parental origin of balanced translocation does not significantly affect the PGT-SR outcomes. It was found that the minimum number of blastocysts required to obtain at least one normal/balanced embryo is 3.5 for balanced translocation carriers. In any genetic counselling before the initiation of PGT-SR, couples should be informed that the probability of obtaining one euploid embryo is low if fewer than 4 blastocysts are biopsied.

      Uncited Reference

      • Dechanet C.
      • Castelli C.
      • Reyftmann L.
      • Hamamah S.
      • Hedon B.
      • Dechaud H.
      • Anahory T.
      Do female translocations influence the ovarian response pattern to controlled ovarian stimulation in preimplantation genetic diagnosis?.

      Appendix. Supplementary materials

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      Biography

      Jing Tong concluded her medical studies at the School of Medicine, Shanghai Jiao Tong University, in 2009. In 2017, she obtained her PhD degree under the supervision of Zi-Jiang Chen. She is now working at a large reproductive medicine centre in China, as an instructor and attending physician.
      Key message
      The parental origin of translocation does not significantly affect the PGT-SR outcomes for young balanced translocation carriers. At least 3.5 blastocysts are required to obtain one euploid embryo. Couples should be informed that the probability of obtaining one euploid embryo is low when fewer than 4 blastocysts are obtained in one PGT cycle.