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PGT-SR
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This entry is adapted from the peer-reviewed paper 10.3390/dna3010004

Preimplantation genetic testing for structural rearrangements (PGT-SR) was one of the first applications of PGT, with initial cases being worked up in the Delhanty lab. It is the least well-known of the various forms of PGT but nonetheless provides effective treatment for many carrier couples. Structural chromosomal rearrangements (SRs) lead to infertility, repeated implantation failure, pregnancy loss, and congenitally affected children, despite the balanced parent carrier having no obvious phenotype. A high risk of generating chromosomally unbalanced gametes and embryos is the rationale for PGT-SR, aiming to select for those that are chromosomally normal, or at least balanced like the carrier parent. PGT-SR largely uses the same technology as PGT-A, i.e., initially FISH, superseded by array CGH, SNP arrays, Karyomapping, and, most recently, next-generation sequencing (NGS). Trophectoderm biopsy is now the most widely used sampling approach of all PGT variants, though there are prospects for non-invasive methods. In PGT-SR, the most significant limiting factor is the availability of normal or balanced embryo(s) for transfer. Factors directly affecting this are rearrangement type, chromosomes involved, and sex of the carrier parent. De novo aneuploidy, especially for older mothers, is a common limiting factor.

PGT-SR chromosome translocation inversion

1. Introduction

Structural chromosomal rearrangements (SRs) are either observed as segmental aneuploidy (extra or missing parts of chromosomes) when unbalanced or, when balanced, usually presenting as a relatively normal phenotype, only discovered when the individual tries to conceive [1]. In other words, carriers of SRs are prone to infertility, repeated miscarriage, and recurrent stillbirth as well as babies with severe congenital disorders including developmental delay [2]. Men with balanced SRs may present with compromised semen parameters and the subsequent fertility issues that can ensue [3]. The fertility problems that can arise when either partner has an SR are variable (indeed they can even vary when siblings carry the same SR). Factors that can also contribute to the infertility phenotype include rearrangement type (translocation, inversion, etc.), the chromosome(s) in question, and chromosomal breakage points. Other factors that have been discussed include sex, age, family history, semen parameters, ovarian reserve, and the presence of an interchromosomal effect (ICE) [4]. ICE is a concept based on an observation that goes as far back as 1963; suggesting that structural abnormalities may affect the segregation of other chromosomes that are not involved in the rearrangement, increasing the likelihood of whole chromosomal or segmental abnormalities [5]. Prenatal diagnosis is, of course, available to carriers; however, like all forms of PGT, PGT-SR exists for couples who do not feel they can have an elective termination of a fetus affected with segmental aneuploidy. The first “patient work-up” of a putative PGT-SR patient appears in a Delhanty-supervised Ph.D. thesis [6] and the original fluorescence in situ hybridization (FISH) strategy (see later) was, a Delhanty invention. PGT-SR by FISH was, for some time, a relatively mainstream activity and, unlike other forms of PGT, a relatively uncontroversial variant of IVF treatment. The first multi-center analysis collated by the European Society of Human Reproduction and Embryology (ESHRE) consortium included 4253 treatment cycles for the first ten years of PGT-SR (1997 until 2007) [7]. Since 2007, collating consortium numbers has become impractical but, as new technologies such as array comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) come online, numbers are undoubtedly increasing. The various biopsy techniques are common to all forms of PGT and the diagnostic techniques (in addition to FISH, aCGH, and NGS) also included single-nucleotide polymorphism (SNP) arrays (chips). For detailed overviews, see the following: [8][9].

2. Balanced SRs in Overview

SRs arise as a result of chromosomal breaks that subsequently rejoin in a different chromosomal location [10]. Derivative chromosomes thereby ensue, rearranging the gene order and linkage patterns. Any chromosome may participate in an SR; however, certain genomic regions are more prone to breakage. Mechanisms include DNA double-strand break repair employing non-homologous end-joining (NHEJ) [10], non-allelic homologous recombination (NAHR) [11][12], chromothripsis [1][13], microhomology-mediated break-induced replication (MMBIR), and fork stalling and template switching (FoSTeS) [14]. Also implicated is chemical or radiation exposure, and the nuclear organization of the chromosome territories [15]. The types of chromosome rearrangement usually found for PGT-SR cases are covered in the next section and individuals usually inherit SRs from their parents [16][17]. The rate of inherited balanced SR is thought to be around 0.27% in fetuses (assayed by prenatal diagnosis) compared to de novo balanced SRs at 0.076–0.096% [16].

3. Robertsonian Translocations

Robertsonian translocations (RobT) are formed by the fusion of two acrocentric chromosomes (13, 14, 15, 21, and/or 22) reducing the number of chromosomes in the karyotype to 45. The reported RobT incidence is 1/1085 live births [2][3]. During the first meiotic division, derivative and normal chromosomes form a trivalent configuration leading to either alternate, adjacent, or, rarely, 3:0 segregation patterns.

4. Reciprocal Translocations

Reciprocal translocations (RecT) arise when non-homologous chromosomes exchange and produce two derivative (der) chromosomes. Their incidence is estimated to be 1 in 600 (0.17%) liveborns [18] but much higher (5.7%) among couples that suffer recurrent miscarriages [2]. During meiosis, the two derivatives, plus the two homologous unaffected chromosomes, adopt a quadrivalent conformation. Segregation patterns during meiosis I are similar in principle to RobTs except that five major segregation outcomes are possible: alternate, adjacent-1, adjacent-2, 3:1, and 4:0, leading to at least sixteen outcomes.
Oocytes are hard to come by for research purposes and thus rarely studied; therefore, the majority of works on chromosome segregation of RecTs and RobTs use sperm. Human–hamster sperm–oocyte fusion to achieve karyotyping [19] was superseded by fluorescence in situ hybridization (FISH) because of the relative technical simplicity and ability to look at a much greater number of cells [20]. Comparative limitations, however, include the number of chromosomes that can be analyzed and difficulties in evaluating the signals. Comprehensive chromosomal analysis of sperm is also possible using techniques such as aCGH and NGS, however, there are significant cost implications [21]. In one such study, 43 individual spermatozoa from a man carrying a balanced reciprocal translocation between chromosomes 2 and 12 have been analyzed using the aCGH technique. Segmental aneuploidy pertaining to the translocation regions was observed in 18.6% of the gametes, compared to alterations in other chromosomes in 16.3% [21]. A remarkable heterogeneity in the proportion of unbalanced sperm and segregational characteristics was observed between studies. For instance, analyzing 136 reciprocal translocation heterozygotes in various studies led to the detection of unbalanced spermatozoa at a range of 19–91% of gametes [22]. A further factor is that reduction of genetic recombination within the pairing cross decreases the proportion of balanced/normal gametes [23]. The same quadrivalent can display different chiasmata distributions varying from person to person. In other words, each RobT/RecT carrier carries an individual risk in terms of their reproductive outcome. Therefore, for PGT-SR, patients should be properly advised by a genetic counselor, with reference to the outcomes that could arise as a result of their SR. The percentage of unbalanced gametes in RobT/RecT carriers could then be used to assist in the calculations of predictive value on embryonic outcomes in which there appears to be a strong correlation [24].

5. Inversions

Inversions involve two breaks within the same chromosome and subsequent reorientation of the resultant piece in the opposite direction (with a change in gene order). Pericentric inversions (PEI) span the centromere, whereas paracentric inversions (PAI—incidence 0.1–0.5%) do not [25]. As with translocations, considerable reproductive risks are associated with PAI and PEI. Severity depends on the chromosomes involved and the size and distribution of the inverted segment. The meiotic configuration associated is an inversion loop. In PAIs, an odd number of chiasmata in the loop leads to acentric fragments (which are lost eventually) and dicentric bridges. In PEIs, partial duplication and deletion of the distal parts of the inversion lead to segmental aneuploidy [26]. PAIs produce fewer unbalanced gametes; in general terms, recombination is reduced in the inversion loop [27][28] and the proportion of unbalanced gametes may be associated with segment size [29][30]. The proportion of unbalanced gametes arising from inversion carriers can be as little as zero, up to slightly over 50% [22].
The most commonly reported inversion is the chromosome 9 PEI, specifically an inversion of the heterochromatic region from the q to the p arm of the chromosome, believed to occur in between 0.25% and 3.5% of the population (presumably dependent on the population studied [31]). Whether this is an inconsequential variant or clinically significant is up for debate, with some studies conflicting. Associations with infertility, repeated pregnancy loss, cancer, congenital abnormalities, and growth retardation, however, appear in the literature [32].
In general terms, when considering inversions as a whole, the risk to reproductive outcome is dependent on the chromosome involved, the size of the inverted segment, and the recombination rate within the pairing loop [29][30][32]—all factors for a genetic counselor to take into account.

6. Insertional Translocations and Complex Chromosomal Rearrangements

Balanced insertional translocations arise via the introduction of part of a chromosome into another non-homologous counterpart. As with other types of SR, sperm FISH might provide a useful guide to assess the risk for male carriers, assisting genetic counselors [33]. The rarity of this type of SR, however, means that meaningful data is limited [34][35].
Complex chromosomal rearrangements constitute SRs not involved in any of the above. They can be double translocations, triple, quadruple, etc. [36]. In the case of triple SRs, hexavalent meiotic configurations form [36]—the chances of balanced gamete formation reduce with increasing complexity, presenting significant challenges to genetic counselors advising PGT-SR patients.

7. Practicing PGT-SR

PGT-SR is offered to SR-carrying patients as an alternative to prenatal diagnosis. Numerous sampling approaches and genomic analysis techniques have been used to isolate normal (or at least chromosomally balanced) embryos. PGT-SR techniques mostly benefitted from the advancement of PGT-A techniques, which use similar technologies. The following sections summarize these.

8. Invasive Sampling Methods for PGT-SR

Sampling methods include polar body biopsy, blastomere (cleavage-stage) biopsy, and trophectoderm (blastocyst-stage) biopsy [7][8][37], each with its unique pros and cons. Polar body biopsy can only be used for maternal carriers and is especially useful when legislation in certain countries precludes embryo analysis [37][38]. Cleavage-stage biopsy became the most popular method until 2005, but has since been discontinued due to disadvantages such as a limited number of cells available for analysis, increased risk of misdiagnosis due to high rates of mosaicism, and possible damage to the embryo. For nearly more than one decade, trophectoderm biopsy is predominantly used not only for its many advantages in terms of cost, and availability of a greater number of cells for analysis, but also for being less likely to damage the embryo [39]. However, one recent study claims that when performed correctly, the impact of biopsy and subsequent vitrification of the cleavage-stage embryos are similar to blastocysts in terms of cell viability, spindle/chromosome configuration, and ultrastructural safety of the organelles of the embryo [40].

9. Minimally Invasive Sampling Methods for PGT-SR

Blastocoel fluid or spent medium act as alternative sources for DNA sampling [41][42]. Blastocentesis concordance rates with trophectoderm samples are thought to be around 97%; however, amplification rates (~82%) are far from optimal [41]. Assessment of spent culture medium for PGT-SR has been reported as successful in a male RobT (14:15) carrier resulting in a live birth of a karyotypically normal, healthy child [43]. Jiao et al. [44] performed PGT-SR on mixed blastocoel fluid/spent medium, trophectoderm, and whole embryo samples using multiple annealing and looping-based amplification cycle (MALBAC) A total of 41 blastocysts from 22 couples with SRs were successfully analyzed for segmental aneuploidy, achieving a high resolution (~1 Mb) without maternal contamination [44].

10. FISH for PGT-SR

FISH is the original diagnostic approach used for PGT-SR, and is less controversial than PGT-A, as it is a targeted approach. it was Joy Delhanty who first devised the classic detection protocol for FISH-based PGT-SR, involving the identification of usually centromeric and sub-telomeric regions with fluorescent probes. This, in turn, was an adaptation of the pioneering work using X- and Y-chromosome probes for sex selection [45], and for aneuploidy [46]. The strategy mostly involved cytogenetic analysis of interphase cells, with a three-color strategy (e.g., with one centromeric and two sub-telomeric or two centromeric and two sub-telomeric probes) [47][48][49].
Such a protocol is, however, limited by the need for pre-clinical work-up on metaphase chromosomes of peripheral blood carriers to confirm the breakpoints and test the efficiency of probes, which is time-consuming and expensive. The need for fixation of blastomeres or trophectoderm cells also limits the procedure, as a good quality nucleus free of surrounding cytoplasm depends on the technical skills of the operator to avoid non-specific signals, suboptimal hybridization, and auto-fluorescing artifacts. Several fixation methods are published, but the most common [50] involves hypotonic solution and 3:1 methanol-acetic acid. A major limitation of this approach is the inability to detect chromosomes not involved in the rearrangement [51] and thus FISH for PGT-SR is mostly now obsolete. It nonetheless still has a place for cryptic translocations and inversions when breakpoints are <2 Mb from the telomere.
Until comprehensive chromosomal analysis techniques, such as array-based and NGS systems came along, researchers tried to improve the informativity of the FISH system both quantitatively (adding extra probes for aneuploidy) and qualitatively, such that it could also distinguish a balanced chromosome complement from a normal one. For this reason, carrier-specific probes were developed to be used in interphase cells [47]. This approach was based on the hybridization of breakpoints usually spanning commercial DNA probes; however, it requires a major pre-clinical work-up, developing those probes for each specific translocation. Another approach was using FISH on metaphase chromosomes from single blastomeres using conversion via nuclear transfer or chemical solutions [52][53]. In order to create metaphase preparations, single blastomeres were fused with enucleated or intact mouse zygotes (nuclear transfer) or were treated with caffeine and colcemid [53]. The nuclear transfer technique was applied to 437 blastomeres, of which 88% resulted in successful nuclear conversion and 29% in clinical pregnancy rate per transfer, with 7 healthy deliveries in 52 cycles [52]. In a larger study, including the results of the previous experience, a chemical conversion method was applied to 946 blastomeres in 94 cycles with 71% efficiency, leading to a conversion rate that decreased spontaneous abortion by 13–15% compared to their PB1/PB2 control group (25%) [53]. Nevertheless, this technique is labor-intensive, limited by the availability of fertilized mouse zygotes and the efficiency of the conversion method.
Most of the PGT-SR with FISH was performed without additional aneuploidy screening [54][55] and thus only a few have yielded results of chromosomal abnormalities unrelated to the parental error [56][57][58]. The rate of abnormalities not involved in translocations has been found to be relatively frequent in embryos obtained from RobT carriers and was higher than in RecT carriers (67% vs. 22%) [56]. In another study, an overall 60.3% aneuploidy rate was found after the analysis of five chromosomes (13, 16, 18, 21, and 22) in cleavage-stage embryos of 13 RecT carriers [57]. Only 8.7% of them were both normal/balanced or euploid for the five chromosomes, and thus transferable. Here, the aneuploidy rate was similar when compared between genders and between age groups (≤37 and >37 years old) but differed among normal/balanced embryos and unbalanced embryos. Aneuploid embryos were more likely to have an unbalanced complement, suggesting a global disruption of mitotic and meiotic segregations of chromosomes. Embryo transfer was performed for nine carriers but no clinical pregnancy was achieved in this cohort. In another study, aneuploidy screening was performed in RecT carriers for chromosomes 13, 18, 21, X, and Y, and revealed that 46.8% of 141 embryos were aneuploid. The live birth rate was 26.7% per embryo transfer; however, the authors concluded that additional aneuploidy screening did not improve the clinical outcomes [58].
The reproductive history of rearrangement carrier couples before PGT-SR treatment is mostly unsuccessful with live-born delivery rates of around 4.8–9.7% [58]. Numerous manuscripts claim to observe a live birth rate increase and a miscarriage rate decrease after PGT-SR when compared to normal (non-assisted) conception. Munne et al. [48] reported PGT-SR in 35 cases, demonstrably improving spontaneous abortions from 92% in natural conceptions to 12.5% for PGT-SR cycles (p < 0.001). This was mirrored in further studies post-PGT-SR, a 24.7% implantation rate, plus an 18.6% miscarriage rate was observed, improving the “take-home baby rate” from 11.5% to 81.4% [52] and to 85.7% [48].
Despite these rare, successful studies, attempts to improve FISH were limited, possibly due to the prevailing use of cleavage-stage biopsy at the time [39]. The ESHRE PGD consortium data reported an overall clinical pregnancy rate of 12–17% per oocyte retrieved and 22–26% per embryo transferred [6]. Using a systematic review approach, reproductive success with PGT-SR was compared with natural conceptions in similar balanced chromosome rearrangement carriers [59]. This encompassed four studies with 469 cases of natural conception plus 21 studies with 126 PGT-SR cases. The cumulative live birth rate was 33–60% (median 34%) in the natural conception group, whereas after PGT-SR, it was a maximum range of 0% to 100% (median 31%). The miscarriage rate showed a modest, but not statistically significant, improvement, namely 21–40% (median 34%) in natural conception and 0–50% (median 0%) following PGT-SR. A further meta-analysis [60] showed similar live birth rates, time to first conception, and miscarriage rates seen in natural conception compared to PGT-SR in couples with recurrent pregnancy loss (studies from 1997 to 2014). It is noteworthy that these studies were limited to couples who had had at least two or more miscarriages.

11. STR-Typing for PGT-SR

Short tandem repeat (STR) typing comprises PCR-based methods and multiplex STR markers located on either side of the chromosomal breakpoint [61]. Thorough work-up is required, for each of the cases, unique to the chromosomal rearrangement of interest. Traversa et al. [61] analyzed 29 couples using this method, finding that the proportion of alternate segregation for RecT was 33% and 77% for RobT. Fetal heartbeat rate was 40% (RobT carriers) and 46% (RecT carriers). The approach benefits from providing controls for exogenous DNA contamination and detection of uniparental disomy [62].

12. Comparative Genomic Hybridization (CGH) and Array Comparative Genomic Hybridization (aCGH)

Both FISH and STR-typing were ultimately replaced by array-based methods such as aCGH and SNP arrays. It thereby became feasible, for the first time, to detect aneuploidy and segmental imbalances of all the chromosomes [63][64]. Comparative genomic hybridization (CGH) was primarily introduced as a means of detecting somatic chromosome loss and gain in cancer cells [65]. When applied to embryo biopsies, DNA from single (or small numbers of) cells were amplified using whole-genome amplification (WGA), co-hybridization of red and green fluorescently labeled test and reference DNA preceded application to chromosome preparations and epifluorescence microscopy analysis [66]. The low resolution of this approach (10–25 Mb) [63][67], as well as its laborious and time-consuming nature, meant that its use was limited. Nonetheless, Malmgren et al. [63] looked at 94 biopsied blastomeres from seven couples who were carriers of SRs using this approach. The confirmation rate between CGH and FISH was low, possibly due to near-universal mosaicism and a number of cells with a chaotic chromosome complement. Chromosomal CGH techniques were soon superseded by microarray-based CGH (aCGH), an altogether more simple and automated method [68]. Metaphase chromosome preparations were thus replaced by small dots of DNA (bacterial artificial chromosomes (BACs) or with oligonucleotide sequences. Bespoke software analysis programs assess the red:green ratios, thereby detecting chromosomal losses and gains. An example of how this was analyzed is the BlueFuse Multi software (Illumina, San Diego, CA, USA), which determines the median log2 ratio for each chromosome (and each chromosomal segment). The resolution is 5–10 Mb for BAC arrays (or occasionally 2.5 Mb [69]) to 20–50 kb using oligonucleotide arrays [70], but balanced rearrangements cannot be identified. In a paper comparing chromosomal CGH, aCGH (BACs), and aCGH (oligonucleotides) analyzing cleavage-stage embryos, all three approaches gave similar profiles, albeit with the oligo-array providing the highest resolution (~20 kb) [70].
aCGH also permits simultaneous detection of other de novo losses and gains, unrelated to the chromosome abnormality of the carrier parent [51][69][71]. It is thus an altogether more effective method than interphase FISH, given that around a quarter of embryos that are a result of balanced segregations have an additional chromosome abnormality.
FISH as the “gold standard” for PGT-SR, therefore, was ultimately discontinued in favor of more comprehensive chromosomal screening approaches. One of the earliest studies [69] using FISH achieved a 70.6% clinical pregnancy rate plus a 63.6% implantation rate in a cohort of translocation carrier patients. The first healthy live birth was reported later that year [72] involving 20 cycles (five RobT and nine RecT and two inversion carriers) with a resolution of detection below 3 Mb. All biopsy methods were included (polar body, blastomere, trophectoderm) with 91.8% WGA efficiency. Only 22.3% of embryos were because of chromosome abnormalities involving both the chromosomes of interest (27.3%) and de novo imbalance (28.9%) and 27.3% with both. The cumulative pregnancy rate per embryo transfer was 45.5% and the live birth rate per embryo transfer was 27% with no miscarriages [72]. Christodoulou et al. [71] studied 34 PGT-SR couples (50 cycles, 9 RobTs, 21 RecTs, 2 inversions, 1 insertional translocation, and 1 complex translocation) using trophectoderm biopsy as a starting material. A total of 35.7% of embryos were normal or balanced overall. Regarding the 133 abnormal embryos, 36.1% had an abnormality that arose as a result of malsegregation of the chromosomes rearranged in the carrier parent. Ghevaria et al. [51] established that 55–65% of cleavage-stage embryos (22 cycles, 16 RecT carriers, 7 RobT carriers) displayed extra aneuploidies of chromosomes not involved in the translocation. Subsequent FISH follow-up demonstrated that meiotic aneuploidy was present in 35% of embryos, 47% had mitotic errors, and 15% had both; 63% carried additional de novo chromosomal imbalance. Fodina et al [73] analyzed chromosomal differences in terms of translocation type and of carrier sex in of 10 couples finding the lowest aneuploidy rate in the male carrier group and the highest in the Robertsonian translocation carrier group. The prevalence of chromosomal aberrations was 4.5× greater in the reciprocal, compared to the Robertsonian translocation carrier group. with 4.7× higher aneuploidy rates in female compared to male carrier groups.
PGT-SR, therefore, benefitted from the success of the aCGH era for PGT-A, improving the cumulative pregnancy rate from 40% with FISH [6] to 62%. aCGH, however, eventually gave way to SNP arrays and NGS

13. Karyomapping and SNP Arrays for PGT-SR

A single-nucleotide polymorphism (SNP) is defined as a DNA sequence variant that occurs every one in 1000 nucleotides. A PGT-SR diagnostic SNP microarray would normally consist of around 300,000 features [73]. Assaying parental DNA precedes the establishment of four parental haplotypes for each chromosome region and the subsequent detection of parental origin. Polymorphic genotypes are denoted as AA, AB, and BB at each locus and analyzed in comparison to the human HapMap reference. SNP arrays tend to be denser than CGH arrays, thereby providing higher resolution. SNP arrays were also allowed to distinguish between balanced carriers and normal embryos [74][75]. One possible drawback of this approach is the availability of parent DNA and at least one unbalanced embryo as a reference [76]. To distinguish carrier and normal embryos, informative SNPs within 5 Mb of the chromosomal breakpoints of each chromosome involved in the rearrangement are required [76]. Comparing genotypes at informative SNP loci can also detect uniparental disomy. Karyomapping, base phasing, and haplarhythmisis are advanced techniques based on SNP detection throughout the genome [74][77][78].
Treff et al. [79] looked at 18 couples with balanced RobTs and RecTs treated by PGT-SR following trophectoderm biopsy and SNP array analysis. An implantation rate of 45% along with a cumulative pregnancy rate per embryo transfer of 75% was achieved. This highlighted the value of simultaneous screening for chromosomes not involved in the chromosome rearrangement of the carrier parent. From 122 embryos analyzed, 62 were normal/balanced, with the remaining 23 being aneuploid for another chromosome. van Uum et al. [80] looked at 36 cleavage-stage embryos “cell by cell” that had previously been determined unbalanced by FISH. Subsequent SNP array analysis revealed concordance with the primary FISH diagnosis: 64% were confirmed, 14% were balanced (opposite to the initial diagnosis), and 22% displayed mosaicism. Tan et al. [81] compared the efficacy of SNP arrays performed on blastocyst embryos compared to FISH on cleavage-stage embryos. The approach that employed SNP array demonstrated greater implantation rates (69% compared to 38% for RobT and 74% compared to 39% for RecT) (p < 0.001). Indeed, the SNP-based approach identified more than 15% more chromosomal abnormalities. Moreover, the percentage of transferable embryos was greater using SNP-based approaches. Overall, SNP array approaches are thought to outperform the FISH methods in terms of higher pregnancy rates (cumulative pregnancy rates of 45–70% per transfer [69][77][79]). In a comparison of SNP arrays with aCGH platforms, Tobler et al. [82] looked at day three and day five embryos from RecT carriers, observing statistically significant differences in the proportion of chromosomally balanced embryos, but not in the overall clinical pregnancy rates (60% for SNP arrays, 65% for aCGH). From nearly 500 embryos analyzed, 45% were chromosomally balanced; 24% were balanced or normal for the chromosomes rearranged in the carrier parent, but aneuploid for other chromosomes; 23% only had an imbalance of the chromosomes involved in the parent’s rearrangement, with 8% containing imbalance for both. It was reported that SNP arrays outperformed aCGH, detecting 47% euploid/balanced embryos compared to 39% for aCGH. Combining both SNP arrays and aCGH demonstrated aneuploidy rates higher in cleavage-stage embryos (38%) compared to blastocysts (22%) (p < 0.001). Moreover, the cumulative pregnancy rate is reportedly better using these comprehensive chromosome screening techniques compared to FISH (62% compared to 40%) [6]. Xiong et al. [83] analyzed 169 couples (52 RobT and 117 RecT carriers): 23% of the subsequent embryos that were analyzed were unbalanced (RobT), compared to 52% for RecT. Further analysis revealed 19% of embryos from RobT carriers and 12% from RecT carriers had de novo aneuploidies for chromosomes not involved in the translocation. Idowu et al. [84] looked at 74 PGT-SR cases, establishing a statistical difference in the sex ratio of unbalanced embryos (12% male compared to 24% female, p < 0.05). Contrary to other studies, the percentage of unbalanced embryos did not differ between cleavage stages compared to trophectoderm biopsy groups, nor were they correlated to maternal age. Euploidy rates, however, were significantly lower in the older (≥35) age group in contrast to younger counterparts (19% compared to 29%). Blastocyst embryos (42%) were more likely to be chromosomally normal than cleavage-stage (22%) embryos. Wang et al. [85] looked at 55 RobT PGT-SR cycles and 181 RecT PGT-SR cycles. Applying a regression model analysis, they found a normal/balanced rate of 42% (RobT) and 27% (RecT), similar to Idowu et al. [84] who demonstrated 37% (RobT) and 19% (RecT), respectively. In both manuscripts, cumulative pregnancy rates for embryo transfer were equivalent (44% and 43%, respectively). Zhang et al. [77] examined 11 RobT and RecT families: of 68 blastocysts, 42 were unbalanced or aneuploid with the remainder balanced or normal. Here, 13 embryos were transferred and subsequently analyzed by (amnio) prenatal diagnosis; this confirmed the initial PGT-SR. Zhang et al. [86] applied BasePhasing in two RecT families and, of 18 blastocysts, eight were unbalanced and 10 balanced/normal; two transfers followed, corroborated by amniocentesis. Beyer et al. [87] used Karyomapping in a PGT-SR setting, successfully establishing it to be applicable for distinguishing normal/balanced outcomes from unbalanced.
Taking all of the studies combined, the SNP-based approach has proven to be an effective methodology for PGT-SR, with the added bonus that it can detect balanced translocation carrier embryos. Whether such detection is morally appropriate, however, is another question and covered later.

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Darren K. Griffin
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