THE INCIDENCE AND TYPE OF CHROMOSOMAL
TRANSLOCATIONS FROM PRENATAL DIAGNOSIS
OF 3800 PATIENTS IN THE REPUBLIC OF MACEDONIA Vasilevska M1,*, Ivanovska E1, Kubelka Sabit K1, Sukarova-Angelovska E2, Dimeska G3 *Corresponding Author: Marinela Vasilevska, M.Sc., Department of Diagnostic Laboratories, Clinical Hospital
Acibadem-Sistine, Skupi 5A, 1000 Skopje, Republic of Macedonia; Tel.: +389-2-3099-511; Fax: +389-2-
3099-599; vasilevskam@acibademsistina.com.mk page: 23
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DISCUSSION
Chromosomal translocations are represented in
our study with an overall frequency of 0.42%. The frequency
of translocations in a balanced state were 0.29%
and of translocations in an unbalanced state was 0.13%.
There were seven Robertsonian translocations
detected in our study, six of them being inherited
from a parent who was a carrier of a Robertsonian
translocation. All four detected rob(13;14) were in
a balanced state. Three of them were of maternal
origin, and in all cases there was no evidence of reproductive
problems. One case of rob(13;14) was
of paternal origin, and the analyzed pregnancy was
achieved by assisted reproduction because of the father’s
severe oligoastenozoospermia. The two cases
of rob(14;21) detected in our study were in an unbalanced
state and of maternal origin.
Our results correlate with the European collaborative
study [4], where all karyotypes of 280 prenatal
samples [parent rob(13;14) carrier] were in a
balanced state. It was noted by several investigators
that meiotic segregation products in male carriers of
all Robertsonian translocations result mostly from
alternate segregation mode (>75.0%) [5-7]. Analysis
of meiotic prophase cells in heterozygous carriers of
different Robertsonian translocations showed that
the predominance of a preferential cis-configuration
of the meiotic trivalent structure could promote alternate
segregation [8,9].
The risk for translocation trisomy 21 (Down’s
syndrome) at amniocentesis in female heterozygote
was estimated to be about 15.0% [4,10]. The risk of
having a live-born child with translocation trisomy 21
was around 10.0%. There was an about 1.0% risk for
paternal transmission of translocation trisomy 21 [2].
In our study, there was one case of de novo unbalanced
homologous translocation with karyotype
46,XY, rob(13;13)(q10;q10)+13. The histopathological
findings of this terminated pregnancy confirmed a
Patau’s syndrome phenotype. According to the consulted references, 90.0% of cases with t(13;13) are de
novo and estimated mutation rate for de novo t(13;13)
is 0.5% per 105 gametes at conception [11]. Bugge et
al. [12] used 20 polymerase chain reaction (PCR)-
based DNA polymorphisms to determine whether
trisomy 13 due to de novo rea(13q;13q) in six cases
is caused by translocation (13q;13q) or isochromosome
(13q;13q), and the determine the parental origin
of the rearrangements and the mechanisms of
formation. In five cases, isochromosomes with two
identical q arms were revealed, one of maternal origin
and four of paternal origin. Only one case had a
Robertsonian translocation of maternal origin [12].
Reciprocal translocations of different autosome
chromosomes were presented in our study with six
cases in a balanced state, five of them of paternal origin
and one double translocation inherited from the
mother. Only the cases of 46,XY,t(6;10)(p21;q26)
pat. and double transloca-tion 46,XX,t(1;21)t(7;16)
mat. were associated with reproductive problems.
All other cases were of paternal origin and did not
report reproductive abnormalities; they have other
children with normal phenotypes.
It was noted that if the same (balanced) karyotype
found in the carrier parent was detected at prenatal
diagnosis, there was no increased risk of phenotypic
abnormality in the child [2]. However, there are
mechanisms where apparently balanced translocation
may have phenotypic consequences in the progeny of
translocation carriers. These are: cryptic unbalanced
defect [13], post zygotic loss of a derivative chromosome
in one cell line [14], position effect [15], and
uniparental disomy. Gametogenesis of reciprocal
translocation carriers is affected by different segregation
modes at meiosis and unbalanced gametes lead
to infertility, recurrent miscarriages and fetal multiple
malformations. Genetic counselling for prenatal
cytoge-netic diagnosis in all future pregnancies of a
parent heterozygous for reciprocal translocation is
required. Genetic counselling for a double translocation
is the same as for a single translocation, although
the risk for future pregnancies is increased [16].
We found two unbalanced karyotypes with reciprocal
translocations. One unbalanced state was
the result of monosomy X (Turner syndrome) associated
with translocation (2;21) of unknown origin.
If there is a parent carrier of the same translocation,
this karyotype may be the result of ICE (interchromosomal
effect) [17].
The other one is a de novo 45,XY,t(18;21)
(p11;p11) 18p- (IVF pregnancy) in parents with normal
karyotypes. Random error in parental gametogenesis
seems to be the reason for this translocation
and the recurrence risk is low.
Regarding the normal phenotype of the girl
with the de novo apparently balanced sex chromosome
translocation 46,X,t(X;10)(p11.23;q22.3), we
can assume that there was early replication of the
translocated X chromosome in all cells. However,
reproductive failure and recurrent miscarriages can
be expected later in life and genetic counselling as
well as prenatal diagnosis is required.
Sex chromosome translocations (X-autosome) are
distinct from autosome translocations because of transcriptional
silencing of an extra X chromosome in the female
[18]. Inactivation pattern is crucial for phenotypes
of affected female carriers. Silencing of a normal X
chromosome is required for a normal phenotype. Even
so, there is a risk of gene disruption or position effect in
X-autosome female carriers. In the review of 122 cases
of balanced X-autosome translocations in females [19],
with respect to the X inactivation pattern, the position
of the X breakpoint and the resulting phenotype, there
were 77.0% of the patients where translocated X chromosome
was replicated early in all cells analyzed. The
breakpoints in these cases were distributed all along the
X chromosome. Most of these patients were either phenotypically
normal or had gonadal dysgenesis, some had
single gene disorders, and less than 9.0% had multiple
congenital anomalies and/or mental retardation. In the
remaining 23.0% of the cases, the translocated X chromosome
was late replicating in a proportion of the cells.
In these cells, only one of the translocation products was
reported to replicate late, while the remaining portion of
the X chromosome showed the same replication pattern
as the homologous part of the active, structurally normal
X chromosome. The analysis of DNA methylation
in one of these cases confirmed non inactivation of the
translocated segment. Consequently, these cells were
functionally disomic for a part of the X chromosome.
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