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
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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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