Chromosome segregation of human non-homologous Robertsonian translocations: insights from preimplantation genetic testing

Chromosome segregation of human non-homologous Robertsonian translocations: insights from preimplantation genetic testing | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Chromosome segregation of human non-homologous Robertsonian translocations: insights from preimplantation genetic testing Peter Benn, Katrina Merrion This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4254475/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Sep, 2024 Read the published version in European Journal of Human Genetics → Version 1 posted 10 You are reading this latest preprint version Abstract Robertsonian translocations (RTs) are associated with a high risk for unbalanced segregations. Preimplantation Genetic Testing (PGT) offers an early opportunity to evaluate segregation patterns and selection against chromosome imbalances. The objective of this study was to evaluate the chromosome complements in blastocysts for male and female RT carriers and provide information useful in PGT counseling for RT carriers. PGT results were reviewed for 296 couples where a balanced and non-homologous RT was present in one member of the couple. All embryos had day 5/6 trophectoderm biopsy and SNP-based PGT. The study included 2,235 blastocysts, of which 2,151 (96.2%) had results. Significantly fewer blastocysts were available for female RT carriers (mean 4.60/IVF cycle) compared to males (5.49/cycle). Male carriers were more likely to have blastocysts with a normal/balanced chromosome complement; 84.8% versus 62.8% (P < 0.00001). Male carriers had fewer blastocysts with monosomy (60/152, 39.5%) compared to female carriers (218/396, 55.1%) (P = 0.001). 21 (1%) blastocysts showed 3:0 segregation; these were mostly double trisomies and derived from female carriers. Differences between chromosome complements for males versus female carriers suggest that selection against unbalanced forms may occur during spermatogenesis. Six blastocyst samples showed an unexpected (“non-canonical”) combination of trisomy and monosomy One case of uniparental disomy was identified. For female carriers, there was no association between unbalanced segregation and parental age but for male carriers, there was an inverse association. PGT is a highly beneficial option for RT carriers and patients can be counseled using our estimates for the chance of at least one normal/balanced embryo. Robertsonian translocation Preimplantation genetic testing Segregation Meiosis Blastocysts Trisomy Monosomy Figures Figure 1 Introduction The short arms of the human acrocentric chromosomes (numbers 13, 14, 15, 21 and 22) contain ribosomal DNA repeats and other pseudo-homologous sequencies. Their close proximity at interphase nucleoli and the presence of inverted sequences renders them susceptible to exchanges that are referred to as Robertsonian translocations (RTs). ( 1 ) These chromosome translocations are the most common specific rearrangements encountered in humans,( 2 ) with an overall frequency of approximately 1 in 800 individuals. ( 3 ) Rob(13;14) and Rob(14;21) are the most common types seen. Although RTs involve the loss of acrocentric short DNA sequencies, RT carriers with 45 chromosomes show no phenotypic consequences, and their karyotypes are often described as “balanced” and “euploid.” However, there are reproductive consequences. For those with RTs involving homologs (homologous translocation), essentially all conceptions are expected to be trisomic or monosomic for the long arm sequences of the relevant chromosomes which is expected to result in either a non-viable embryo, lack of implantation, pregnancy loss, or specific syndromes at birth (notably, trisomy 21 (Down syndrome) and trisomy 13 (Patau syndrome)). ( 4 , 5 ) Carriers of RTs involving nonhomologous chromosomes (heterologous translocation) can have normal offspring but are at increased risk for infertility, ( 6 ) pregnancy loss, ( 7 ) and, for those involving chromosomes 21 or 13, livebirths with Down syndrome or Patau syndrome, respectively. ( 8 ) Segregation of RTs is based on the notion that translocated chromosomes are not able to pair correctly at meiosis 1 and a trivalent structure arises. ( 9 ) Chromosomes then segregate in an alternate pattern (resulting in normal or balanced gametes) or an adjacent pattern, resulting in either trisomy or monosomy (for either of the involved chromosomes) in the zygote. It is also possible that all 3 chromosomes segregate together which will result in double trisomy or double monosomy in the zygote. Preimplantation genetic testing for aneuploidy (PGT-A) or for structural rearrangements (PGT-SR) is offered to couples where one parent is known to be a carrier of a RT, as this can potentially improve clinical pregnancy and outcomes. ( 10 ) Early studies on blastomere samples analyzed by fluorescence in situ hybridization (FISH) showed high levels of unbalanced translocations compared to blastocyst samples analyzed by microarrays, and this was interpreted as evidence for early selection against embryos with imbalances. ( 11 , 12 ) More recent studies, mostly on blastocysts, have established that the proportion of normal/balanced translocation embryos is higher for male carries compared to female carriers. ( 13 – 18 ) Previous studies have also shown that the is no parental age effect in the segregation of RTs.( 13 ); ( 14 , 19 ) Jia et al ( 15 ) concluded that there was no significant difference in the segregation rates for the different RTs; however, this conclusion was based on a relatively small dataset. In this study, we reviewed the chromosome complements of blastocyst samples from a large set of patients referred to a single commercial reference laboratory for PGT where the indication for testing was a balanced RT in one member of the couple. We provide evidence that segregation and/or selection results in chromosome complements in embryos that can be more complex than previously recognized. We also consider the clinical implications of our observations. Methods This retrospective cohort study included PGT data from blastocyst samples received between April 2011 and May 2023 at a single reference laboratory with the indication of a parental balanced RT. Parental translocation type, as confirmed by cytogenetic karyotype analysis, was reviewed for each referred case. In vitro fertilization (IVF) cycles and day 5/6 trophectoderm biopsies on blastocysts were performed by the referring IVF clinics. Blastocyst samples and biological parent blood, buccal, or sperm samples were shipped for analysis. PGT for the parental translocation with concurrent 24 chromosome aneuploidy screening was performed using Illumina CytoSNP-12b microarrays with Parental Support bioinformatics, as previously described.( 20 ) In brief, this method utilizes parental SNP genotype information to predict the possible SNP genotypes for an embryo. The testing algorithms compare the observed SNP data with the predicted allele distributions for different copy number hypotheses and identifies the maximum likelihood copy number for each chromosome. This analysis allows for detection of monosomy, trisomy or higher polysomy, haploidy, triploidy, large segmental deletions/duplications, uniparental disomy (UPD), and parental origin of abnormalities. This methodology does not allow for differentiation between an embryo that is normal (euploid) versus balanced. Data was compiled for each patient’s IVF/PGT cycle and included information on which RT was present, which parent was a carrier, parental ages at the time of testing, number of blastocyst samples analyzed, and the genetic findings. Results were classified as “unbalanced” if monosomy or trisomy of the correct parental origin was present for a chromosome involved in the RT and “normal” if no chromosome imbalance was detected. “Sporadic aneuploidy” was defined as aneuploidy involving chromosomes not involved in the translocation or involving a translocation homolog but derived from the parent not carrying the RT. Statistical analyses were performed using online calculators. Differences in proportions were tested with the T-test for independent ratios ( https://www.socscistatistics.com/tests/ztest/ ), Chi-square test was used for differences between grouped data ( https://www.socscistatistics.com/tests/chisquare2/default2.aspx ) with Fisher exact test for small numbers ( https://www.socscistatistics.com/tests/fisher/default2.aspx ), Mann-Whitney test for ordinal data ( https://www.socscistatistics.com/tests/mannwhitney/ ), and Cochran-Armitage Chi-square test for linear trend ( https://epitools.ausvet.com.au/trend ). To evaluate the probability of at least one normal/balanced blastocyst in a specific number evaluated, a binomial distribution calculator was used ( https://stattrek.com/online-calculator/binomial?utm_content=cmp-true ). Confidence intervals were based on the adjusted Wald method ( https://measuringu.com/calculators/wald/ ). Results There were 296 couples referred for PGT because either the female (55.1%; 163/296) or the male (44.9%; 133/296) partner was a carrier of a non-homologous RT. Table 1 summarizes the tested translocations, carrier parent ages at the time of testing, utilization of repeat cycles, re-biopsy samples tested, and the rate of testing without results. Table 1 Types of RTs, number of cycles, patient age, blastocysts for the study population All RT carriers Female carriers Male carriers Total patients 296 163 133 Rob(13;14) 198 106 92 Rob(13;15) 11 7 4 Rob(13;21) 6 0 6 Rob(13;22) 6 1 5 Rob(14;15) 8 6 2 Rob(14;21) 48 32 16 Rob(14;22) 9 6 3 Rob(15;21) 4 1 3 Rob(15;22) 5 3 2 Rob(21;22) 1 1 0 Total cycles 448 254 194 Without a repeat cycle 299 167 132 Repeat cycles 149 87 62 Number re-biopsies 16 10 6 Mean maternal age 1 34.8 34.8 34.8 Mean paternal age 1 37.0 36.9 37.2 Blastocysts with results 2151 1126 1025 Blastocysts without results 84 43 41 1. Age at the time of the in vitro fertilization cycle. Age was re-calculated when there was a repeat cycle. Table 2 summarizes the average number of blastocysts analyzed per cycle for Rob(13;14), Rob(14;21), and all RTs combined. There were significantly fewer embryos when the carrier was maternal compared to paternal (average 4.60 versus 5.49 per IVF cycle, respectively), with the deficit largely associated with Rob(13;14). This did not appear to be attributable to age-related decline in female fertility; there was no significant difference between the age of female carriers and females with a carrier partner (mean 34.84 years versus mean 34.81 years, P = 0.873). Table 2 Blastocysts per cycle for female and male carriers of Robertsonian translocations Cycles Blastocysts 1 Average Blastocysts/cycle Female vs Male carriers P 2 All Rob Female carriers 254 1169 4.60 P = 0.038 Male carriers 194 1066 5.49 Rob(13;14) Female carriers 168 773 4.60 P = 0.016 Male carriers 133 746 5.61 Rob(14;21) Female carriers 44 237 5.39 P = 0.865 Male carriers 23 131 5.70 1. Includes blastocysts without successful analysis. 2. Mann Whitney Test for the number of blastocysts in each cycle. The segregation products in the blastocysts with successful analysis are summarized in Table 3 . Male carriers were significantly more likely to have blastocysts with a chromosomally balanced chromosome complement (alternate segregation); balanced rates were 84.8% for male carriers versus 62.8% female carriers (P < 0.00001). Subset analysis restricted to Rob(13;14) and Rob(14;21) showed that the higher frequency of balanced products for male carriers was present for each of these more common RT types. Table 3 Summary of the observed segregation products in the blastocysts from RT carriers Segregation Female carriers Male carriers Blastocysts (%) All RT All 1126 (100) 1025 (100) Alternate 707 (62.8) 869 (84.8) All adjacent 396 (35.2) 152 (14.9) Monosomy 218 (19.4) 60 (5.9) Trisomy 178 (15.8) 92 (9.0) 3:0 17 (1.5) 4 (0.4) Non-canonical 6 (0.5) 0 (0) Rob(13;14) All 743 (100) 720 (100) Alternate 475 (63.9) 617 (85.7) All adjacent 251 (33.8) 103 (14.3) Monosomy 13 61 (8.2) 23 (3.2) Trisomy 13 48 (6.5) 34 (4.7) Monosomy 14 79 (10.6) 13 (1.8) Trisomy 14 63 (11.5) 33 (4.6) 3:0 12 (1.6) 0 (0) Non-canonical 5 (0.7) 0 (0) Rob (14:21) All 228 (100) 125 (100) Alternate 133 (58.3) 101 (80.8) All adjacent 93 (41.0) 24 (19.2) Monosomy 14 9 (3.9) 6 (4.8) Trisomy 14 10 (4.4) 4 (3.2) Monosomy 21 41 18.0) 6 (4.8) Trisomy 21 33 14.5) 8 (6.4) 3:0 1 (0.4%) 0 (0) Non-canonical 1 (0.4%) 0 (0) Table 3 also shows the breakdown of monosomy versus trisomy in the segregations interpreted as adjacent. For all RTs combined, the proportion of blastocysts that had monosomy was significantly lower for male carriers (60/152, 39.5%) than for female carriers (218/396, 55.1%) (test for two independent proportions, P = 0.001). However, this difference was dependent on the specific type of RT. For Rob(13;14), the same pattern was observed; less monosomy was seen for chromosomes 13 or 14 for male carriers (36/103, 35.0%) compared to monosomy of chromosomes 13 or 14 for female carriers (140/251, 55.8%) (P = 0.0004). For Rob(14;21), no such difference was evident; monosomy for chromosome 14 or 21 for male carriers (12/24, 50%) versus monosomy of chromosome 14 or 21 for female carriers (50/93, 53.8%) (P = 0.74). There was also evidence for non-random segregation products for the 21 blastocysts with chromosome complements consistent with 3:0 segregation (16 with double trisomy and 5 with double monosomy). For maternal carriers, 16 cases of apparent 3:0 segregation involved double trisomy and one case showed double monosomy. In contrast, no double trisomy was observed for paternal carriers, but four double monosomies were detected (Fisher exact test, P < 0.05). In six blastocysts (0.7%), there was a combination of a trisomy and a monosomy that was incompatible with the eight theoretically possible segregation products that can arise during segregation of a RT. We refer to these as “non-canonical”. All six were products from maternal carriers: five involved Rob(13;14) with trisomy 13 and monosomy 14 and one involved t(14;21) with trisomy 14 and monosomy 21. There was only one case of UPD observed in our dataset. This case involved a male carrier of a Rob(15;21) with a UPD( 15 )mat blastocyst sample.. To provide robust data for genetic counseling for individuals with Rob(13;14) and Rob(14;21), we combined our observations on the chance of a balanced segregation with the cases from two other recent papers (Table 4 ). We then calculated the probability of at least one normal blastocyst using a binomial calculator, under the assumption that each embryo was fully independent of others from the same patient. These observations showed that for the average referral with four to six blastocysts available (Table 2 ), PGT should substantially increase the chance of being able to select for a balanced embryo. These calculations did not include sporadic chromosome abnormalities unrelated to the RT. Table 4 Overall chance for a normal/balanced (alternate) segregation for RT carriers with calculation of at least one normal/balanced segregation when multiple blastocysts are available. Reference Segregation Females with Rob(13;14) Males with Rob(13;14) Females with Rob(14;21) Males with Rob(14;21) Zhang et al.2021 All 261 314 45 87 Alternate 183 260 37 50 Adjacent 77 53 7 35 3:0/others 1 1 1 2 Dang et al., 2023 All 968 1059 395 191 Alternate 596 869 219 165 Adjacent 365 186 167 26 3:0/others 7 4 9 0 Current study All 743 720 228 125 Alternate 475 617 133 101 Adjacent 251 103 93 24 3:0/others 17 0 2 0 All studies combined All 1972 2093 668 403 Alternate 1254 1746 389 316 Adjacent 693 342 267 85 3:0/others 25 5 12 2 Overall proportion Alternate %, (95% CI) 63.6 (61.3–65.5) 83.4 (81.8–85.0) 58.2 (54.4–61.8) 78.4% (74.1–82.2) Probability (%) of ≥ 1 balanced blastocyst a : 1 blastocyst available 63.6 83.4 58.2 78.4 2 blastocysts available 86.6 97.2 82.4 95.3 3 blastocysts available 95.1 99.5 92.6 99.0 4 blastocysts available 98.2 > 99.9 96.9 99.8 5 blastocysts available 99.3 > 99.99 98.7 > 99.9 a. Does not include risk for a sporadic abnormality unrelated to the translocation. To explore a potential association between carrier age and segregation patterns, the data for female and male carriers was separately analyzed, with data grouped into 3-year age ranges. Figure 1 a shows that there is no trend in the rate of unbalanced segregations for maternal carriers across the different maternal age groups (Armitage-Cochran test, P = 0.58, slope = 0.006). Since maternal and paternal ages are correlated, the observed lack of an age association seen for paternal age was expected and seen (P = 0.23, slope = 0.014) (Fig. 1 b). To further look for evidence of a maternal age effect, we considered only 3:0 segregations from female carriers. For the 17 cases (16 cycles) with 3:0 segregation in blastocysts from female carriers, the mean maternal age at the time of testing was 34.6 years compared to 34.8 years for female carriers with other types of segregation (Mann-Whitney test, P = 0.624). For paternal carriers, there was a trend towards lower rates of unbalanced segregations with increasing parental age (Fig. 1 c, d). For paternal age, this did not reach statistical significance (P = 0.052, slope − 0.017) but for maternal age, a stronger trend was observed (P = 0.0035, slope − 0.026) which differed significantly from linearity and indicated a likely non-linear relationship. To assess whether unbalanced RTs were associated with increased levels of other chromosome abnormalities (interchromosomal effect), .( 10 , 21 ) or reduced levels due to reduced viability of embryos with multiple chromosome imbalances, we assessed the rate of sporadic chromosome abnormalities (i.e., unrelated to the RT). When the embryo had an unbalanced RT, the rate of sporadic abnormalities was 38.7%. For those embryos that were balanced or normal for the RT chromosomes, the rate of sporadic abnormalities was 42.8%. The difference between the two rates did not reach statistical significance (P = 0.086). Discussion In this study, we reviewed the chromosome complements of embryos from individuals referred for PGT-SR because either the male or female was known to be a carrier of a RT. We show that the chromosomes observed did not necessarily correspond to the expected classical view of how segregation of RTs occurs. Specifically, we document trisomy plus monosomy, higher than expected monosomies compared to trisomies, and differences in 3:0 segregation (double trisomy versus double monosomy) depending on the sex of the carrier parent. We also provide relatively robust estimates for the probability of at least one chromosomally balanced embryo when PGT is offered. Contemporary views of chromosome segregation at meiosis recognize that precocious separation of chromatids, anaphase lag, reverse segregation, and non-disjunction have a role in the formation of aneuploidy.( 22 ) In addition, high rates of early mitotic error (zygote or earliest embryonic divisions) are present.( 23 ) The propensity for individual whole chromosomes to segregate abnormally at meiosis appears to be inversely correlated with chromosome size.( 24 ) Longer chromosomes have more cohesin holding chromatids together and this is thought to minimize the chance for segregation error.( 22 ) Precocious separation of chromatids is strongly maternal-age dependent while the non-disjunction mechanism, at least for the acrocentric chromosomes, is less dependent on maternal age.( 25 ) Our observations of no maternal age effect in the segregation for unbalanced RTs can perhaps be explained by unbalanced translocation segregation being a similar process to non-disjunction. Alternatively, the heterozygous change in length associated with an RT and the presence of the associated additional cohesin might be sufficient to substantially reduce maternal-age related segregation error. Precocious separation of chromatids, anaphase lag, reverse segregation, and mosaicism may explain the non-canonical chromosome segregation patterns we observed in rare cases. Our observation of differences in the number of embryos, and differences in the chromosome complements, depending on which parent is a carrier, might be explained by basic differences in the meiotic processes in males versus females. Supporting this theory, it has previously been pointed out that even for chromosomally balanced segregations, there appears to be differences in the proportions of normal versus balanced translocation karyotypes.( 26 – 28 ) The excess of RT carriers over normal karyotypes cannot be easily explained by post-meiotic correction of unbalanced segregations. Early somatic cell gain or loss of a chromosome to correct from monosomy or trisomy to disomy is rare; we observed only one case with UPD which can arise due to correction.( 29 ) Post-meiotic selection against unbalanced chromosome compliments in spermatogenesis is also possible and this might explain the lower proportion of unbalanced embryos for male carriers compared to female carriers. Male carriers of RTs have increased rates of infertility and may show reduced sperm counts, perhaps reflecting the selection against imbalances, notably spermatids and sperm with nullisomy. ( 30 ) Our observation of higher rates of alternate segregation (and an excess of trisomy relative to monosomy), for the blastocysts from male carriers would be consistent with this explanation. FISH studies on sperm from RT carriers have shown more alternate segregation gametes compared to adjacent segregation gametes.( 31 ) We also observed lower rates of unbalanced RTs in the blastocysts for older male carriers, suggesting that the selection processes in males may also be affected by other factors that reduce sperm counts.( 32 ) Selection against embryos and fetuses through miscarriage further reduces the relative proportion of unbalanced conceptions. Most autosomal monosomic conceptions are believed to be lost very early in pregnancy, and surviving autosomal trisomies depend on the gene imbalance with highest survival for trisomies 21, 18, and 13. ( 33 ) It is therefore useful to compare ratios of trisomy to normal/balanced in blastocysts versus later in pregnancy. For example, for Rob(13;14) the ratio of trisomy 13 to normal/balanced blastocysts for female carriers was 48:475 (approximately 1:10) and for male carriers was 34:617 (approximately 1:18) (Table 3 ). In the second trimester, trisomy 13 arising from a Rob(13;14) is approximately 1–2%.( 25 ) This level of reduction from embryo to the second trimester is surprising given that trisomy 13 can potentially survive to birth. In the case of Rob(14;21), the ratio of trisomy 21 to normal/balanced karyotypes in blastocysts from female carriers was 33:133 (approximately 1:4) and for male carriers 8:101 (approximately 1:8) (Table 3 ). In the second trimester, risk for trisomy 21 has been estimated to be 12:80 (approximately 1:7) for females but only 1:37 for male carriers.( 25 ) More robust data is needed to better establish whether or not there is a differential effect on the viability of an embryo or pregnancy depending on the parent of origin of the chromosomes. Our observations have direct clinical application. We show that PGT is highly advantageous to individuals with RTs because, in most instances, there will be sufficient normal/balanced embryos (Tables 2 and 4 ). Strong differences exist between female versus male carriers, and risk for a surviving fetus with an imbalance will differ depending on the specific RT. Although male carriers of RTs often show reduced sperm count and lower sperm mobility, they can be assured that the potential for an embryo with a normal/balanced segregation is relatively high. Probabilities for a normal blastocyst can be separately provided for Rob(13;14) and Rob(14;21). We suggest that for the rarer RT types, counseling is based on all RT combined, at least until more information is available on their segregation patterns. Caution is needed because these other forms may, at least in part, be rarer because of a higher rate of unbalanced gametes. In an era where most chromosome abnormalities are identified through molecular techniques that do not identify balanced translocations, our study serves as a reminder of the clinical value of ruling out RT segregation when Down syndrome and Patau syndrome is diagnosed. A strength of this study was the use of SNP microarray technology which included parental genotype information to determine the origin of each chromosome in the blastocysts. Thus, our data provided the ability to differentiate whether a chromosome abnormality involving one of the chromosomes of the RT was from the carrier parent (unbalanced segregation) vs. non-carrier parent (an unrelated sporadic aneuploidy), and to identify UPD. Our study was based on a large set of referrals which allowed us to separately analyze Rob(13;14) and Rob(14;21). Our study also has some limitations. The molecular genetic approach was not used to distinguish between the two possible alternate segregation patterns, normal versus a balanced translocation. How the carriers were initially ascertained (e.g., infertility, history of spontaneous abortion(s), an affected child, or secondary finding in cytogenetic studies for other indications) is unknown and it is possible that the cases referred are not representative of all RT carriers in the population. Information on the use of ovarian stimulation, notably for female carriers, ( 34 ), number of oocytes retrieved, and other clinical or laboratory data that might have affected referrals or IVF success rates was not available to us. Our interpretation of embryos showing segregation patterns is based primarily on the classical expectations and it is possible that, in addition to the above noted non-canonical examples, more imbalances could be attributable to precocious chromatid separation, anaphase lag, reverse segregation, or an early mitotic error. This study does not include a control population to assess the number of embryos for non-carrier couples. Additionally, when comparing rates in males versus females, we did not consider the (relatively minor) difference in age in carrier females versus carrier males. In summary, we have provided evidence that the segregation for RTs is more complex than previously recognized. In addition to asymmetric segregation at meiosis, there may be complex selection processes from the time of the initial meiotic segregation to the time of early embryo development. We demonstrate the benefit of PGT as a reproductive testing option for RT carriers. Declarations Date availability statement Data will be made available to upon request from Z Demko, Natera, Inc. [email protected] . Code availability Not applicable. Acknowledgements : We thank the Origins of Aneuploidy Research Consortium members for their interest and constructive suggestions. This work was funded by Natera Inc., a provider of reproductive genetic testing. Author Contribution Statement PB was the Principal Investigator, performed the data analysis, and prepared the draft manuscript. KM compiled and generated a summary of the PGT data and provided the methods for the PGT. All authors reviewed the manuscript. Ethical Approval This study was deemed exempt from IRB review by the Institutional Review Board at Ethical and Independent Review Services (ID no. 19040-04). Competing Interests T his study was funded by Natera, Inc. Peter Benn is a consultant for Natera, Inc. with options to own stocks in the company. Katrina Merrion is a full-time employee of Natera, Inc. with stocks in the company. Natera also covers travel expenses to educational meetings. References Guarracino A, Buonaiuto S, de Lima LG, Potapova T, Rhie A, Koren S et al. Recombination between heterologous human acrocentric chromosomes. Nature 2023;617:335-43. Benn P. Prenatal diagnosis of chromosome abnormalities through chorionic villus sampling and amnicentesis. 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Preimplantation genetic testing in couples with balanced chromosome rearrangement: a four-year period real world retrospective cohort study. BMC Pregnancy Childbirth. 2024 Jan 27;24(1):86. doi: 10.1186/s12884-023-06237-6. PMID: 38280990; PMCID: PMC10821259 Dang T, Xie P, Zhang Z, Hu L, Tang Y, Tan Y et al. The effect of carrier characteristics and female age on preimplantation genetic testing results of blastocysts from Robertsonian translocation carriers. J Assist Reprod Genet 2023;40:1995-2002. Johnson DS, Gemelos G, Baner J, Ryan A, Cinnioglu C, Banjevic M et al. Preclinical validation of a microarray method for full molecular karyotyping of blastomeres in a 24-h protocol. Hum Reprod 2010;25:1066-75. Ogur C, Kahraman S, Griffin DK, Yapan CC, Tufekci MA, Cetinkaya M, Temel SG, Yilmaz A. PGT for structural chromosomal rearrangements in 300 couples reveals specific risk factors but an interchromosomal effect is unlikely. Reproductive BioMedicine Online. 2023 Apr 1;46(4):713-27. Charalambous C, Webster A, Schuh M. Aneuploidy in mammalian oocytes and the impact of maternal ageing. Nat Rev Mol Cell Biol 2023;24:27-44. Vanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C et al. Chromosome instability is common in human cleavage-stage embryos. Nat Med 2009;15:577-83. McCoy RC, Demko ZP, Ryan A, Banjevic M, Hill M, Sigurjonsson S et al. Evidence of selection against complex mitotic-origin aneuploidy during preimplantation development. PLoS Genet 2015;11:e1005601. Gruhn JR, Zielinska AP, Shukla V, Blanshard R, Capalbo A, Cimadomo D et al. Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 2019;365:1466-9. Pardo-Manuel de Villena F, Sapienza C. Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations. Hum Genet 2001;108:31-6. Boue A, Gallano P. A collaborative study of the segregation of inherited chromosome structural rearrangements in 1356 prenatal diagnoses. Prenat Diagn 1984;4 Spec No:45-67. Daniel A, Hook EB, Wulf G. Risks of unbalanced progeny at amniocentesis to carriers of chromosome rearrangements: data from United States and Canadian laboratories. Am J Med Genet 1989;33:14-53. Benn P. Uniparental disomy: Origin, frequency, and clinical significance. Prenat Diagn 2021;41:564-72. Chen X, Zhou C. Reciprocal translocation and Robertsonian translocation in relation to semen parameters: A retrospective study and systematic review. Andrologia 2022;54:e14262. Pylyp LY, Zukin VD, Bilko NM. Chromosomal segregation in sperm of Robertsonian translocation carriers. J Assist Reprod Genet 2013;30:1141-5. Halvaei I, Litzky J, Esfandiari N. Advanced paternal age: effects on sperm parameters, assisted reproduction outcomes and offspring health. Reprod Biol Endocrinol 2020;18:110. Benn P, Grati FR. Aneuploidy in first trimester chorionic villi and spontaneous abortions: Windows into the origin and fate of aneuploidy through embryonic and fetal development. Prenat Diagn 2021;41:519-24. Chen SH, Escudero T, Cekleniak NA, Sable DB, Garrisi MG, Munne S. Patterns of ovarian response to gonadotropin stimulation in female carriers of balanced translocation. Fertil Steril 2005;83:1504-9. Additional Declarations (Not answered) Cite Share Download PDF Status: Published Journal Publication published 28 Sep, 2024 Read the published version in European Journal of Human Genetics → Version 1 posted Editorial decision: revise 29 Jul, 2024 Review # 2 received at journal 25 Jul, 2024 Reviewer # 2 agreed at journal 28 Jun, 2024 Review # 1 received at journal 17 May, 2024 Reviewer # 1 agreed at journal 26 Apr, 2024 Reviewers invited by journal 26 Apr, 2024 Submission checks completed at journal 15 Apr, 2024 First submitted to journal 12 Apr, 2024 Unknown event 12 Apr, 2024 Editor assigned by journal 11 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4254475","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":291272596,"identity":"8c0351dc-79ce-47c3-997f-2b4a1635bfb4","order_by":0,"name":"Peter Benn","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAn0lEQVRIiWNgGAWjYBACAxDxgYEhAURLEK2FcQbJWph5SNJizt577LFtm10efwPzwds8xGix7DmXbpzbllwscYAt2ZooLQY3csykc9sOJG5g4DGTJk7L/Tdm0pZgLfzfiNRyA2g4I8QWNuK0WPbkmEn2nEtOnHGYzdhyDjFazNnPmEn8KLNL7G9vfnjjDTFaEICZNOWjYBSMglEwCvABAMrIK8kijc39AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-7917-6946","institution":"University of Connecticut Health Center","correspondingAuthor":true,"prefix":"","firstName":"Peter","middleName":"","lastName":"Benn","suffix":""},{"id":291272597,"identity":"764a4d41-4969-43f8-9ec2-e8e962346e6c","order_by":1,"name":"Katrina Merrion","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Katrina","middleName":"","lastName":"Merrion","suffix":""}],"badges":[],"createdAt":"2024-04-11 22:25:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4254475/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4254475/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41431-024-01693-w","type":"published","date":"2024-09-28T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55767605,"identity":"c13a8696-f178-45c5-b758-8ba36a5e8fc7","added_by":"auto","created_at":"2024-05-02 20:20:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":148163,"visible":true,"origin":"","legend":"\u003cp\u003ex-axis, maternal age group; y-axis proportion (%) with unbalanced segregation. A: Maternal age for female carriers. B: Paternal age for maternal carriers. C: Maternal age for male carriers. D: Paternal age for male carriers. Vertical lines denote 95% confidence intervals.\u003c/p\u003e","description":"","filename":"RobtFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4254475/v1/3351cd1167f820256fbf034a.png"},{"id":65523859,"identity":"7c713068-d515-4b9b-b20a-56debb59cf31","added_by":"auto","created_at":"2024-09-29 07:07:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":779302,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4254475/v1/efe1bd2d-d6be-464d-a968-b93aaaf0e497.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"Chromosome segregation of human non-homologous Robertsonian translocations: insights from preimplantation genetic testing","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe short arms of the human acrocentric chromosomes (numbers 13, 14, 15, 21 and 22) contain ribosomal DNA repeats and other pseudo-homologous sequencies. Their close proximity at interphase nucleoli and the presence of inverted sequences renders them susceptible to exchanges that are referred to as Robertsonian translocations (RTs). (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) These chromosome translocations are the most common specific rearrangements encountered in humans,(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) with an overall frequency of approximately 1 in 800 individuals. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Rob(13;14) and Rob(14;21) are the most common types seen.\u003c/p\u003e \u003cp\u003eAlthough RTs involve the loss of acrocentric short DNA sequencies, RT carriers with 45 chromosomes show no phenotypic consequences, and their karyotypes are often described as \u0026ldquo;balanced\u0026rdquo; and \u0026ldquo;euploid.\u0026rdquo; However, there are reproductive consequences. For those with RTs involving homologs (homologous translocation), essentially all conceptions are expected to be trisomic or monosomic for the long arm sequences of the relevant chromosomes which is expected to result in either a non-viable embryo, lack of implantation, pregnancy loss, or specific syndromes at birth (notably, trisomy 21 (Down syndrome) and trisomy 13 (Patau syndrome)). (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Carriers of RTs involving nonhomologous chromosomes (heterologous translocation) can have normal offspring but are at increased risk for infertility, (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) pregnancy loss, (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and, for those involving chromosomes 21 or 13, livebirths with Down syndrome or Patau syndrome, respectively. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSegregation of RTs is based on the notion that translocated chromosomes are not able to pair correctly at meiosis 1 and a trivalent structure arises. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Chromosomes then segregate in an alternate pattern (resulting in normal or balanced gametes) or an adjacent pattern, resulting in either trisomy or monosomy (for either of the involved chromosomes) in the zygote. It is also possible that all 3 chromosomes segregate together which will result in double trisomy or double monosomy in the zygote.\u003c/p\u003e \u003cp\u003ePreimplantation genetic testing for aneuploidy (PGT-A) or for structural rearrangements (PGT-SR) is offered to couples where one parent is known to be a carrier of a RT, as this can potentially improve clinical pregnancy and outcomes. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Early studies on blastomere samples analyzed by fluorescence in situ hybridization (FISH) showed high levels of unbalanced translocations compared to blastocyst samples analyzed by microarrays, and this was interpreted as evidence for early selection against embryos with imbalances. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) More recent studies, mostly on blastocysts, have established that the proportion of normal/balanced translocation embryos is higher for male carries compared to female carriers. (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Previous studies have also shown that the is no parental age effect in the segregation of RTs.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e); (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) Jia \u003cem\u003eet al\u003c/em\u003e (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) concluded that there was no significant difference in the segregation rates for the different RTs; however, this conclusion was based on a relatively small dataset.\u003c/p\u003e \u003cp\u003e In this study, we reviewed the chromosome complements of blastocyst samples from a large set of patients referred to a single commercial reference laboratory for PGT where the indication for testing was a balanced RT in one member of the couple. We provide evidence that segregation and/or selection results in chromosome complements in embryos that can be more complex than previously recognized. We also consider the clinical implications of our observations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective cohort study included PGT data from blastocyst samples received between April 2011 and May 2023 at a single reference laboratory with the indication of a parental balanced RT. Parental translocation type, as confirmed by cytogenetic karyotype analysis, was reviewed for each referred case. In vitro fertilization (IVF) cycles and day 5/6 trophectoderm biopsies on blastocysts were performed by the referring IVF clinics. Blastocyst samples and biological parent blood, buccal, or sperm samples were shipped for analysis. PGT for the parental translocation with concurrent 24 chromosome aneuploidy screening was performed using Illumina CytoSNP-12b microarrays with Parental Support bioinformatics, as previously described.(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) In brief, this method utilizes parental SNP genotype information to predict the possible SNP genotypes for an embryo. The testing algorithms compare the observed SNP data with the predicted allele distributions for different copy number hypotheses and identifies the maximum likelihood copy number for each chromosome. This analysis allows for detection of monosomy, trisomy or higher polysomy, haploidy, triploidy, large segmental deletions/duplications, uniparental disomy (UPD), and parental origin of abnormalities. This methodology does not allow for differentiation between an embryo that is normal (euploid) versus balanced.\u003c/p\u003e \u003cp\u003eData was compiled for each patient\u0026rsquo;s IVF/PGT cycle and included information on which RT was present, which parent was a carrier, parental ages at the time of testing, number of blastocyst samples analyzed, and the genetic findings. Results were classified as \u0026ldquo;unbalanced\u0026rdquo; if monosomy or trisomy of the correct parental origin was present for a chromosome involved in the RT and \u0026ldquo;normal\u0026rdquo; if no chromosome imbalance was detected. \u0026ldquo;Sporadic aneuploidy\u0026rdquo; was defined as aneuploidy involving chromosomes not involved in the translocation or involving a translocation homolog but derived from the parent not carrying the RT.\u003c/p\u003e \u003cp\u003eStatistical analyses were performed using online calculators. Differences in proportions were tested with the T-test for independent ratios (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.socscistatistics.com/tests/ztest/\u003c/span\u003e\u003cspan address=\"https://www.socscistatistics.com/tests/ztest/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), Chi-square test was used for differences between grouped data (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.socscistatistics.com/tests/chisquare2/default2.aspx\u003c/span\u003e\u003cspan address=\"https://www.socscistatistics.com/tests/chisquare2/default2.aspx\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) with Fisher exact test for small numbers (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.socscistatistics.com/tests/fisher/default2.aspx\u003c/span\u003e\u003cspan address=\"https://www.socscistatistics.com/tests/fisher/default2.aspx\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), Mann-Whitney test for ordinal data (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.socscistatistics.com/tests/mannwhitney/\u003c/span\u003e\u003cspan address=\"https://www.socscistatistics.com/tests/mannwhitney/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and Cochran-Armitage Chi-square test for linear trend (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://epitools.ausvet.com.au/trend\u003c/span\u003e\u003cspan address=\"https://epitools.ausvet.com.au/trend\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). To evaluate the probability of at least one normal/balanced blastocyst in a specific number evaluated, a binomial distribution calculator was used (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://stattrek.com/online-calculator/binomial?utm_content=cmp-true\u003c/span\u003e\u003cspan address=\"https://stattrek.com/online-calculator/binomial?utm_content=cmp-true\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Confidence intervals were based on the adjusted Wald method (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://measuringu.com/calculators/wald/\u003c/span\u003e\u003cspan address=\"https://measuringu.com/calculators/wald/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThere were 296 couples referred for PGT because either the female (55.1%; 163/296) or the male (44.9%; 133/296) partner was a carrier of a non-homologous RT. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the tested translocations, carrier parent ages at the time of testing, utilization of repeat cycles, re-biopsy samples tested, and the rate of testing without results.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTypes of RTs, number of cycles, patient age, blastocysts for the study population\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll RT carriers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale carriers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale carriers\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e296\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(13;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(13;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(13;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(13;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(14;15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(14;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(14;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(15;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(15;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(21;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e194\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWithout a repeat cycle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e299\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRepeat cycles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber re-biopsies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean maternal age\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean paternal age\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocysts with results\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlastocysts without results\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e1. Age at the time of the in vitro fertilization cycle. Age was re-calculated when there was a repeat cycle.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the average number of blastocysts analyzed per cycle for Rob(13;14), Rob(14;21), and all RTs combined. There were significantly fewer embryos when the carrier was maternal compared to paternal (average 4.60 versus 5.49 per IVF cycle, respectively), with the deficit largely associated with Rob(13;14). This did not appear to be attributable to age-related decline in female fertility; there was no significant difference between the age of female carriers and females with a carrier partner (mean 34.84 years versus mean 34.81 years, P\u0026thinsp;=\u0026thinsp;0.873).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBlastocysts per cycle for female and male carriers of Robertsonian translocations\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCycles\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBlastocysts\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAverage Blastocysts/cycle\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFemale vs Male carriers \u003cem\u003eP\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll Rob\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale carriers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale carriers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(13;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale carriers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale carriers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(14;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale carriers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.865\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale carriers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e1. Includes blastocysts without successful analysis.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e2. Mann Whitney Test for the number of blastocysts in each cycle.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe segregation products in the blastocysts with successful analysis are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Male carriers were significantly more likely to have blastocysts with a chromosomally balanced chromosome complement (alternate segregation); balanced rates were 84.8% for male carriers versus 62.8% female carriers (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). Subset analysis restricted to Rob(13;14) and Rob(14;21) showed that the higher frequency of balanced products for male carriers was present for each of these more common RT types.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of the observed segregation products in the blastocysts from RT carriers\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSegregation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale carriers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale carriers\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eBlastocysts (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1126 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1025 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e707 (62.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e869 (84.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll adjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e396 (35.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e152 (14.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonosomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e218 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrisomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e178 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92 (9.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (1.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (0.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-canonical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (0.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob(13;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e743 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e720 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e475 (63.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e617 (85.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll adjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e251 (33.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e103 (14.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonosomy 13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrisomy 13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonosomy 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79 (10.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrisomy 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (1.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-canonical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRob (14:21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e228 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e125 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e133 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e101 (80.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll adjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (41.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (19.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonosomy 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (4.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrisomy 14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (3.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMonosomy 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 18.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (4.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrisomy 21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 14.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (6.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-canonical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e also shows the breakdown of monosomy versus trisomy in the segregations interpreted as adjacent. For all RTs combined, the proportion of blastocysts that had monosomy was significantly lower for male carriers (60/152, 39.5%) than for female carriers (218/396, 55.1%) (test for two independent proportions, P\u0026thinsp;=\u0026thinsp;0.001). However, this difference was dependent on the specific type of RT. For Rob(13;14), the same pattern was observed; less monosomy was seen for chromosomes 13 or 14 for male carriers (36/103, 35.0%) compared to monosomy of chromosomes 13 or 14 for female carriers (140/251, 55.8%) (P\u0026thinsp;=\u0026thinsp;0.0004). For Rob(14;21), no such difference was evident; monosomy for chromosome 14 or 21 for male carriers (12/24, 50%) versus monosomy of chromosome 14 or 21 for female carriers (50/93, 53.8%) (P\u0026thinsp;=\u0026thinsp;0.74).\u003c/p\u003e \u003cp\u003eThere was also evidence for non-random segregation products for the 21 blastocysts with chromosome complements consistent with 3:0 segregation (16 with double trisomy and 5 with double monosomy). For maternal carriers, 16 cases of apparent 3:0 segregation involved double trisomy and one case showed double monosomy. In contrast, no double trisomy was observed for paternal carriers, but four double monosomies were detected (Fisher exact test, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eIn six blastocysts (0.7%), there was a combination of a trisomy and a monosomy that was incompatible with the eight theoretically possible segregation products that can arise during segregation of a RT. We refer to these as \u0026ldquo;non-canonical\u0026rdquo;. All six were products from maternal carriers: five involved Rob(13;14) with trisomy 13 and monosomy 14 and one involved t(14;21) with trisomy 14 and monosomy 21. There was only one case of UPD observed in our dataset. This case involved a male carrier of a Rob(15;21) with a UPD(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)mat blastocyst sample..\u003c/p\u003e \u003cp\u003eTo provide robust data for genetic counseling for individuals with Rob(13;14) and Rob(14;21), we combined our observations on the chance of a balanced segregation with the cases from two other recent papers (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). We then calculated the probability of at least one normal blastocyst using a binomial calculator, under the assumption that each embryo was fully independent of others from the same patient. These observations showed that for the average referral with four to six blastocysts available (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), PGT should substantially increase the chance of being able to select for a balanced embryo. These calculations did not include sporadic chromosome abnormalities unrelated to the RT.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverall chance for a normal/balanced (alternate) segregation for RT carriers with calculation of at least one normal/balanced segregation when multiple blastocysts are available.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSegregation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemales with Rob(13;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMales with Rob(13;14)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFemales with Rob(14;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMales with Rob(14;21)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhang et al.2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e314\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0/others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDang et al., 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e191\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e596\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e869\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0/others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e743\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e720\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e617\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e251\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0/others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll studies combined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1972\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e668\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e403\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlternate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e389\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e316\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdjacent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e693\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e342\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3:0/others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall proportion Alternate %, (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.6\u003c/p\u003e \u003cp\u003e(61.3\u0026ndash;65.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.4\u003c/p\u003e \u003cp\u003e(81.8\u0026ndash;85.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58.2\u003c/p\u003e \u003cp\u003e(54.4\u0026ndash;61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e78.4%\u003c/p\u003e \u003cp\u003e(74.1\u0026ndash;82.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProbability (%) of \u0026ge; 1 balanced blastocyst\u003csup\u003ea\u003c/sup\u003e:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 blastocyst available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e58.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e78.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 blastocysts available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e82.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e95.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 blastocysts available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e92.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e99.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4 blastocysts available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;99.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e99.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 blastocysts available\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e99.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;99.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e98.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;99.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003ea. Does not include risk for a sporadic abnormality unrelated to the translocation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo explore a potential association between carrier age and segregation patterns, the data for female and male carriers was separately analyzed, with data grouped into 3-year age ranges. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ea shows that there is no trend in the rate of unbalanced segregations for maternal carriers across the different maternal age groups (Armitage-Cochran test, P\u0026thinsp;=\u0026thinsp;0.58, slope\u0026thinsp;=\u0026thinsp;0.006). Since maternal and paternal ages are correlated, the observed lack of an age association seen for paternal age was expected and seen (P\u0026thinsp;=\u0026thinsp;0.23, slope\u0026thinsp;=\u0026thinsp;0.014) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). To further look for evidence of a maternal age effect, we considered only 3:0 segregations from female carriers. For the 17 cases (16 cycles) with 3:0 segregation in blastocysts from female carriers, the mean maternal age at the time of testing was 34.6 years compared to 34.8 years for female carriers with other types of segregation (Mann-Whitney test, P\u0026thinsp;=\u0026thinsp;0.624).\u003c/p\u003e \u003cp\u003eFor paternal carriers, there was a trend towards lower rates of unbalanced segregations with increasing parental age (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, d). For paternal age, this did not reach statistical significance (P\u0026thinsp;=\u0026thinsp;0.052, slope \u0026minus;\u0026thinsp;0.017) but for maternal age, a stronger trend was observed (P\u0026thinsp;=\u0026thinsp;0.0035, slope \u0026minus;\u0026thinsp;0.026) which differed significantly from linearity and indicated a likely non-linear relationship.\u003c/p\u003e \u003cp\u003eTo assess whether unbalanced RTs were associated with increased levels of other chromosome abnormalities (interchromosomal effect), .(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eor reduced levels due to reduced viability of embryos with multiple chromosome imbalances, we assessed the rate of sporadic chromosome abnormalities (i.e., unrelated to the RT). When the embryo had an unbalanced RT, the rate of sporadic abnormalities was 38.7%. For those embryos that were balanced or normal for the RT chromosomes, the rate of sporadic abnormalities was 42.8%. The difference between the two rates did not reach statistical significance (P\u0026thinsp;=\u0026thinsp;0.086).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we reviewed the chromosome complements of embryos from individuals referred for PGT-SR because either the male or female was known to be a carrier of a RT. We show that the chromosomes observed did not necessarily correspond to the expected classical view of how segregation of RTs occurs. Specifically, we document trisomy plus monosomy, higher than expected monosomies compared to trisomies, and differences in 3:0 segregation (double trisomy versus double monosomy) depending on the sex of the carrier parent. We also provide relatively robust estimates for the probability of at least one chromosomally balanced embryo when PGT is offered.\u003c/p\u003e \u003cp\u003eContemporary views of chromosome segregation at meiosis recognize that precocious separation of chromatids, anaphase lag, reverse segregation, and non-disjunction have a role in the formation of aneuploidy.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) In addition, high rates of early mitotic error (zygote or earliest embryonic divisions) are present.(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) The propensity for individual whole chromosomes to segregate abnormally at meiosis appears to be inversely correlated with chromosome size.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) Longer chromosomes have more cohesin holding chromatids together and this is thought to minimize the chance for segregation error.(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) Precocious separation of chromatids is strongly maternal-age dependent while the non-disjunction mechanism, at least for the acrocentric chromosomes, is less dependent on maternal age.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) Our observations of no maternal age effect in the segregation for unbalanced RTs can perhaps be explained by unbalanced translocation segregation being a similar process to non-disjunction. Alternatively, the heterozygous change in length associated with an RT and the presence of the associated additional cohesin might be sufficient to substantially reduce maternal-age related segregation error. Precocious separation of chromatids, anaphase lag, reverse segregation, and mosaicism may explain the non-canonical chromosome segregation patterns we observed in rare cases.\u003c/p\u003e \u003cp\u003eOur observation of differences in the number of embryos, and differences in the chromosome complements, depending on which parent is a carrier, might be explained by basic differences in the meiotic processes in males versus females. Supporting this theory, it has previously been pointed out that even for chromosomally balanced segregations, there appears to be differences in the proportions of normal versus balanced translocation karyotypes.(\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) The excess of RT carriers over normal karyotypes cannot be easily explained by post-meiotic correction of unbalanced segregations. Early somatic cell gain or loss of a chromosome to correct from monosomy or trisomy to disomy is rare; we observed only one case with UPD which can arise due to correction.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) Post-meiotic selection against unbalanced chromosome compliments in spermatogenesis is also possible and this might explain the lower proportion of unbalanced embryos for male carriers compared to female carriers. Male carriers of RTs have increased rates of infertility and may show reduced sperm counts, perhaps reflecting the selection against imbalances, notably spermatids and sperm with nullisomy. (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) Our observation of higher rates of alternate segregation (and an excess of trisomy relative to monosomy), for the blastocysts from male carriers would be consistent with this explanation. FISH studies on sperm from RT carriers have shown more alternate segregation gametes compared to adjacent segregation gametes.(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) We also observed lower rates of unbalanced RTs in the blastocysts for older male carriers, suggesting that the selection processes in males may also be affected by other factors that reduce sperm counts.(\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSelection against embryos and fetuses through miscarriage further reduces the relative proportion of unbalanced conceptions. Most autosomal monosomic conceptions are believed to be lost very early in pregnancy, and surviving autosomal trisomies depend on the gene imbalance with highest survival for trisomies 21, 18, and 13. (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) It is therefore useful to compare ratios of trisomy to normal/balanced in blastocysts versus later in pregnancy. For example, for Rob(13;14) the ratio of trisomy 13 to normal/balanced blastocysts for female carriers was 48:475 (approximately 1:10) and for male carriers was 34:617 (approximately 1:18) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In the second trimester, trisomy 13 arising from a Rob(13;14) is approximately 1\u0026ndash;2%.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) This level of reduction from embryo to the second trimester is surprising given that trisomy 13 can potentially survive to birth. In the case of Rob(14;21), the ratio of trisomy 21 to normal/balanced karyotypes in blastocysts from female carriers was 33:133 (approximately 1:4) and for male carriers 8:101 (approximately 1:8) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In the second trimester, risk for trisomy 21 has been estimated to be 12:80 (approximately 1:7) for females but only 1:37 for male carriers.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) More robust data is needed to better establish whether or not there is a differential effect on the viability of an embryo or pregnancy depending on the parent of origin of the chromosomes.\u003c/p\u003e \u003cp\u003eOur observations have direct clinical application. We show that PGT is highly advantageous to individuals with RTs because, in most instances, there will be sufficient normal/balanced embryos (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Strong differences exist between female versus male carriers, and risk for a surviving fetus with an imbalance will differ depending on the specific RT. Although male carriers of RTs often show reduced sperm count and lower sperm mobility, they can be assured that the potential for an embryo with a normal/balanced segregation is relatively high. Probabilities for a normal blastocyst can be separately provided for Rob(13;14) and Rob(14;21). We suggest that for the rarer RT types, counseling is based on all RT combined, at least until more information is available on their segregation patterns. Caution is needed because these other forms may, at least in part, be rarer because of a higher rate of unbalanced gametes. In an era where most chromosome abnormalities are identified through molecular techniques that do not identify balanced translocations, our study serves as a reminder of the clinical value of ruling out RT segregation when Down syndrome and Patau syndrome is diagnosed.\u003c/p\u003e \u003cp\u003eA strength of this study was the use of SNP microarray technology which included parental genotype information to determine the origin of each chromosome in the blastocysts. Thus, our data provided the ability to differentiate whether a chromosome abnormality involving one of the chromosomes of the RT was from the carrier parent (unbalanced segregation) vs. non-carrier parent (an unrelated sporadic aneuploidy), and to identify UPD. Our study was based on a large set of referrals which allowed us to separately analyze Rob(13;14) and Rob(14;21).\u003c/p\u003e \u003cp\u003eOur study also has some limitations. The molecular genetic approach was not used to distinguish between the two possible alternate segregation patterns, normal versus a balanced translocation. How the carriers were initially ascertained (e.g., infertility, history of spontaneous abortion(s), an affected child, or secondary finding in cytogenetic studies for other indications) is unknown and it is possible that the cases referred are not representative of all RT carriers in the population. Information on the use of ovarian stimulation, notably for female carriers, (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), number of oocytes retrieved, and other clinical or laboratory data that might have affected referrals or IVF success rates was not available to us. Our interpretation of embryos showing segregation patterns is based primarily on the classical expectations and it is possible that, in addition to the above noted non-canonical examples, more imbalances could be attributable to precocious chromatid separation, anaphase lag, reverse segregation, or an early mitotic error. This study does not include a control population to assess the number of embryos for non-carrier couples. Additionally, when comparing rates in males versus females, we did not consider the (relatively minor) difference in age in carrier females versus carrier males.\u003c/p\u003e \u003cp\u003eIn summary, we have provided evidence that the segregation for RTs is more complex than previously recognized. In addition to asymmetric segregation at meiosis, there may be complex selection processes from the time of the initial meiotic segregation to the time of early embryo development. We demonstrate the benefit of PGT as a reproductive testing option for RT carriers.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDate availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Data will be made available to upon request from Z Demko, Natera, Inc. [email protected].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNot applicable.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: \u0026nbsp;We thank the Origins of Aneuploidy Research Consortium members for their interest and constructive suggestions. This work was funded by Natera Inc., a provider of reproductive genetic testing.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor Contribution Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePB was the Principal Investigator, performed the data analysis, and prepared the draft manuscript. KM compiled and generated a summary of the PGT data and provided the methods for the PGT. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was deemed exempt from IRB review by the Institutional Review Board at Ethical and Independent Review Services (ID no. 19040-04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT\u003c/strong\u003ehis study was funded by Natera, Inc.\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003ePeter Benn is a consultant for Natera, Inc. with options to own stocks in the company. Katrina Merrion is a full-time employee of Natera, Inc. with stocks in the company. Natera also covers travel expenses to educational meetings.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGuarracino A, Buonaiuto S, de Lima LG, Potapova T, Rhie A, Koren S\u003cem\u003e et al.\u003c/em\u003e Recombination between heterologous human acrocentric chromosomes. Nature 2023;617:335-43.\u003c/li\u003e\n\u003cli\u003eBenn P. Prenatal diagnosis of chromosome abnormalities through chorionic villus sampling and amnicentesis. In: Milunsky A, Milunsky, JM. (eds). Genetic Disorders of the Fetus. 8\u003csup\u003eth\u003c/sup\u003e Edition. Chichester: Wiley Blackwell, 2021. pp 404-498.\u003c/li\u003e\n\u003cli\u003ePoot M, Hochstenbach R. Prevalence and phenotypic impact of Robertsonian translocations. Mol Syndromol 2021;12:1-11. \u003c/li\u003e\n\u003cli\u003eDallaire L, Fraser FC. Two unusual cases of familial mongolism. Can J Genet Cytol 1964;6:540-7.\u003c/li\u003e\n\u003cli\u003eGardner RJ, Parslow MI, Veale AM. 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J Assist Reprod Genet 2023;40:1995-2002.\u003c/li\u003e\n\u003cli\u003eJohnson DS, Gemelos G, Baner J, Ryan A, Cinnioglu C, Banjevic M\u003cem\u003e et al.\u003c/em\u003e Preclinical validation of a microarray method for full molecular karyotyping of blastomeres in a 24-h protocol. Hum Reprod 2010;25:1066-75.\u003c/li\u003e\n\u003cli\u003eOgur C, Kahraman S, Griffin DK, Yapan CC, Tufekci MA, Cetinkaya M, Temel SG, Yilmaz A. PGT for structural chromosomal rearrangements in 300 couples reveals specific risk factors but an interchromosomal effect is unlikely. Reproductive BioMedicine Online. 2023 Apr 1;46(4):713-27.\u003c/li\u003e\n\u003cli\u003eCharalambous C, Webster A, Schuh M. Aneuploidy in mammalian oocytes and the impact of maternal ageing. Nat Rev Mol Cell Biol 2023;24:27-44.\u003c/li\u003e\n\u003cli\u003eVanneste E, Voet T, Le Caignec C, Ampe M, Konings P, Melotte C\u003cem\u003e et al.\u003c/em\u003e Chromosome instability is common in human cleavage-stage embryos. Nat Med 2009;15:577-83.\u003c/li\u003e\n\u003cli\u003eMcCoy RC, Demko ZP, Ryan A, Banjevic M, Hill M, Sigurjonsson S\u003cem\u003e et al.\u003c/em\u003e Evidence of selection against complex mitotic-origin aneuploidy during preimplantation development. PLoS Genet 2015;11:e1005601.\u003c/li\u003e\n\u003cli\u003eGruhn JR, Zielinska AP, Shukla V, Blanshard R, Capalbo A, Cimadomo D\u003cem\u003e et al.\u003c/em\u003e Chromosome errors in human eggs shape natural fertility over reproductive life span. Science 2019;365:1466-9.\u003c/li\u003e\n\u003cli\u003ePardo-Manuel de Villena F, Sapienza C. Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations. Hum Genet 2001;108:31-6.\u003c/li\u003e\n\u003cli\u003eBoue A, Gallano P. A collaborative study of the segregation of inherited chromosome structural rearrangements in 1356 prenatal diagnoses. Prenat Diagn 1984;4 Spec No:45-67.\u003c/li\u003e\n\u003cli\u003eDaniel A, Hook EB, Wulf G. Risks of unbalanced progeny at amniocentesis to carriers of chromosome rearrangements: data from United States and Canadian laboratories. Am J Med Genet 1989;33:14-53.\u003c/li\u003e\n\u003cli\u003eBenn P. Uniparental disomy: Origin, frequency, and clinical significance. Prenat Diagn 2021;41:564-72.\u003c/li\u003e\n\u003cli\u003eChen X, Zhou C. Reciprocal translocation and Robertsonian translocation in relation to semen parameters: A retrospective study and systematic review. Andrologia 2022;54:e14262.\u003c/li\u003e\n\u003cli\u003ePylyp LY, Zukin VD, Bilko NM. Chromosomal segregation in sperm of Robertsonian translocation carriers. J Assist Reprod Genet 2013;30:1141-5.\u003c/li\u003e\n\u003cli\u003eHalvaei I, Litzky J, Esfandiari N. Advanced paternal age: effects on sperm parameters, assisted reproduction outcomes and offspring health. Reprod Biol Endocrinol 2020;18:110.\u003c/li\u003e\n\u003cli\u003eBenn P, Grati FR. Aneuploidy in first trimester chorionic villi and spontaneous abortions: Windows into the origin and fate of aneuploidy through embryonic and fetal development. Prenat Diagn 2021;41:519-24.\u003c/li\u003e\n\u003cli\u003eChen SH, Escudero T, Cekleniak NA, Sable DB, Garrisi MG, Munne S. Patterns of ovarian response to gonadotropin stimulation in female carriers of balanced translocation. Fertil Steril 2005;83:1504-9.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Robertsonian translocation, Preimplantation genetic testing, Segregation, Meiosis, Blastocysts, Trisomy, Monosomy","lastPublishedDoi":"10.21203/rs.3.rs-4254475/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4254475/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRobertsonian translocations (RTs) are associated with a high risk for unbalanced segregations. Preimplantation Genetic Testing (PGT) offers an early opportunity to evaluate segregation patterns and selection against chromosome imbalances. The objective of this study was to evaluate the chromosome complements in blastocysts for male and female RT carriers and provide information useful in PGT counseling for RT carriers.\u003c/p\u003e \u003cp\u003ePGT results were reviewed for 296 couples where a balanced and non-homologous RT was present in one member of the couple. All embryos had day 5/6 trophectoderm biopsy and SNP-based PGT. The study included 2,235 blastocysts, of which 2,151 (96.2%) had results.\u003c/p\u003e \u003cp\u003eSignificantly fewer blastocysts were available for female RT carriers (mean 4.60/IVF cycle) compared to males (5.49/cycle). Male carriers were more likely to have blastocysts with a normal/balanced chromosome complement; 84.8% versus 62.8% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). Male carriers had fewer blastocysts with monosomy (60/152, 39.5%) compared to female carriers (218/396, 55.1%) (P\u0026thinsp;=\u0026thinsp;0.001). 21 (1%) blastocysts showed 3:0 segregation; these were mostly double trisomies and derived from female carriers. Differences between chromosome complements for males versus female carriers suggest that selection against unbalanced forms may occur during spermatogenesis. Six blastocyst samples showed an unexpected (\u0026ldquo;non-canonical\u0026rdquo;) combination of trisomy and monosomy One case of uniparental disomy was identified. For female carriers, there was no association between unbalanced segregation and parental age but for male carriers, there was an inverse association.\u003c/p\u003e \u003cp\u003ePGT is a highly beneficial option for RT carriers and patients can be counseled using our estimates for the chance of at least one normal/balanced embryo.\u003c/p\u003e","manuscriptTitle":"Chromosome segregation of human non-homologous Robertsonian translocations: insights from preimplantation genetic testing","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-02 20:19:56","doi":"10.21203/rs.3.rs-4254475/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-07-29T09:51:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-07-25T11:21:18+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-28T08:05:55+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-05-17T08:31:39+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-26T16:47:16+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-04-26T16:31:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-15T08:48:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Human Genetics","date":"2024-04-12T14:11:40+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-04-12T11:26:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-11T22:21:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-human-genetics","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejhg","sideBox":"Learn more about [European Journal of Human Genetics](http://www.nature.com/ejhg/)","snPcode":"41431","submissionUrl":"https://mts-ejhg.nature.com/cgi-bin/main.plex","title":"European Journal of Human Genetics","twitterHandle":"@ejhg_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"633c8cc2-beb5-4156-896d-b72e28f02b49","owner":[],"postedDate":"May 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-29T07:07:41+00:00","versionOfRecord":{"articleIdentity":"rs-4254475","link":"https://doi.org/10.1038/s41431-024-01693-w","journal":{"identity":"european-journal-of-human-genetics","isVorOnly":false,"title":"European Journal of Human Genetics"},"publishedOn":"2024-09-28 04:00:00","publishedOnDateReadable":"September 28th, 2024"},"versionCreatedAt":"2024-05-02 20:19:56","video":"","vorDoi":"10.1038/s41431-024-01693-w","vorDoiUrl":"https://doi.org/10.1038/s41431-024-01693-w","workflowStages":[]},"version":"v1","identity":"rs-4254475","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4254475","identity":"rs-4254475","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}