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
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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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