THE LARGEST PARACENTRIC INVERSION, THE HIGHEST RATE OF RECOMBINANT SPERMATOZOA. CASE REPORT: 46,XY, inv(2)(q21.2q37.3) AND LITERATURE REVIEW
Yapan CC, Beyazyurek C, Ekmekci CG, Kahraman S
*Corresponding Author: Cigdem Cinar Yapan, MSc., Reproductive Genetics Laboratory, Istanbul Memorial Hospital, Piyalepasa Street, 34385 Sisli, Istanbul, Turkey. Tel.: +90-212-314-6666. Fax: +90-212-314-6657. E-mail: cigdemcinar78@gmail.com
page: 55

DISCUSSION

Although PAIs are generally considered to be harmless without phenotypic consequences in carriers [10], recombination can occur during gametogenesis, can cause genetically unbalanced gametes, and subsequently, unbalanced embryos. This could cause repeated IVF failures or repeated pregnancy loss, which is more frequently seen among inversion carriers compared to the normal population. Despite apparently being “balanced,” an inversion might disrupt a critical gene and cause an associated phenotype [21,22]. Furthermore, small cryptic deletions or duplications around breakpoints may have an effect on the phenotype. In our case, the length of the inverted segment was the largest one reported in other PAI cases published to date. The inverted segment contained almost 43.0% of the whole chromosome and was approximately 103 Mbp in length. Subsequently, sperm-FISH analysis revealed 28.0% of recombinant spermatozoa, which was the highest rate among PAI carriers published in the literature. Our results are in line with the previous observations, supporting a clear correlation between the size of the inverted segment and the frequency of the recombinant spermatozoa (Table 2). Some previous studies have mentioned that a significant level of unbalanced gametes would require a minimum inversion size of 100 Mbp and minimum segment proportion of 50.0% of the chromosome [23,24] for pericentric inversions (PEIs). Morel et al. [24], suggested that significant number of recombinants are produced when the inverted segment size is >50.0% of the total length of the inverted chromosome. For PAIs, however, there is not enough data regarding the factors affecting segregation. Our findings show that a significant rate of unbalanced gametes can be detected even if the inverted segment size was less than 50.0% of the whole chromosome (42.5%). Recently, Bhatt et al. [25], mentioned that the formation of recombinants depends on the presence and number of hot spots (HSs) and the recombination frequency in the particular region. These are called HSs, high recombination rate spot (HRS) and very high recombination rate spot (VHRS). The higher the number of recombination HSs around the breakpoints, within the inverted segment, the higher the probability of formation of double crossovers and recombination [25]. Breakpoints were in critical regions for our case. One of them was in or around a HS (2q21.2) and the other was probably in a VHRS (2q37.3). All this knowledge contributes to explain our high recombination rate. Interchromosomal effect has been investigated in a few previous studies with a maximum of five chromosomes including 13, 18, 21, X and Y and was demonstrated in some studies (e.g., [15]) whilst not in others [12,16]. To the best of our knowledge, this is only the second study (after Anton et al. [15]), in which significantly high ICE has been found in a PAI carrier. In this study, an especially high aneuploidy rate for chromosome 17 was found. Inversion loops have been shown to be associated with other chromosome pairs [26]. The high rate of aneuploidy for chromosome 17 found in this study could be attributed to an ICE due to an association of inversion loop with chromosome 17 by a mechanism similar to which Batanian and Hulten [26] proposed. In male carriers, sperm FISH studies allow counselors to offer patients better reproductive genetic advice prior to a PGD cycle. Information of unbalanced spermatozoa rate can provide tips for counseling on the genetic risk of infertility. A 5.0% technical error rate for FISH applications must be taken into consideration when counseling patients. Although imbalances due to recombination could easily be detected with the FISH technique, small deletions that might occur at or near the inversion breakpoints could not be detected, unless direct sequencing of the breakpoint regions have been performed. For the couples with an increased rate of unbalanced gametes, the PGD technique offers a healthy pregnancy, eliminating unbalanced or aneuploid embryos from transfer. With the use of more recent techniques such as array-comparative genomic hybridization (a-CGH), it is possible to select the normal or balanced embryos and also exclude ICE by analyzing all 24 chromosomes in one day [27]. However, the embryos of our patient were not suitable for biopsy since they had a poor embryonic development. It is well known that most early losses are associated with chromosomal abnormalities in sperm or egg, and result in arrested embryonic development and/or failed implantation [28]. Such a poor development might be the consequence of the high rates of recombinant gametes, variety of unpredictable unbalanced chromosome products and small microscopic deletions that could have resulted from the PAI. In addition, in our case, multiple crossover events could be likely for this large and susceptible segment to recombination. Our results support that not every PAI is innocent as they could be the reason of high abnormality rates in sperm that might have been associated with repeated IVF failures and pregnancy losses. To date, the possibility of associations of PAI on chromosome 2 with fertility and sexual developmental problems have been discussed in several reports [14,29-31]. However, how far the impact of PAIs on poor obstetrics history should be further evaluated in order to be demonstrated as the primary cause of the infertility in this couple. This study demonstrated the importance of sperm FISH evaluation in the genetic counseling and assisted reproductive technology (ART) practices. It also gives further evidence of a possible ICE and a possible impact of additive consequences on fertility in PAI carriers.



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