Probability rates for different pregnancy outcomes in carriers of reciprocal chromosomal translocations involving chromosome 13

OBJECTIVES: The aim of study was to estimate the probability rates for unfavorable pregnancy outcomes in carriers of reciprocal chromosomal translocations involving 13 chromosome (RCT-13q). MATERIAL AND METHODS: We collected total empirical data about 232 pregnancies of 56 carriers coming from 28 pedigrees. RCT classification was based on classic cytogenetic methods for interpretation of breakpoint position. The probability rates of particular type of pathology related to the total number of pregnancies after ascertainment correction have been calculated with the help of Stengel-Rutkowski and Stene method. RESULTS: The risk figures for unbalanced offspring after 2:2 disjunction and adjacent-1 segregation for the whole group of pedigrees were calculated as 5.2 +/- 1.7% (9/173)--medium risk, for maternal (MAT) and paternal (PAT) carriers were about 6.2 +/- 2.3% (7/173) and 4.8 +/- 3.3% (2/42) respectively. Considering different segment lengths of 13q, similar values for shorter and longer segments were obtained [4.3 +/- 1.9% (5/115) for 13q21-->qter and 7.0 +/- 3.3% (4/58) for 13q12-->qter]. The risk figures for miscarriages as 36.4 +/-3.6% (63/173) and for stillbirths/early death as 4.6 +/- 31.6% (8/173) were obtained. The risk figures for unbalanced offspring after 3:1 disjunction were calculated as 7.7 +/- 7.45 (9/13). Conclusions: 1. Risk figures for different pregnancy outcomes are differ among particular forms of pathology. 2. Probability rate for unbalanced progeny at birth was calculated as a medium risk and similar values for carriers of different segments of 13q were obtained. 3. Probability rate for miscarriages was high but risk for stillbirths/early deaths of newborn was low. 4. No differences in values of rate for particular forms of pathology were found for maternal and paternal carriers of RCT-13q.     

Analysis of chromosome abnormalities in sperm and embryos from two 45,XY,t(13;14)(q10;q10) carriers

Robertsonian translocation t(13q14q) is studied in sperm and embryos of two couples undergoing preimplantation genetic diagnosis (PGD) in which both males are carriers of the translocation. It is already known that the chances of achieving pregnancy for a translocation carrier are directly linked to the number of normal or balanced embryos available for replacement. In our work it was found that the frequency of balanced spermatozoa was almost identical in both patients (74 and 77%), and after PGD, the frequencies of abnormal embryos caused by the translocation were also similar. Sperm chromosome analysis in translocation carriers can provide a reasonable basis for estimating a baseline of chromosome abnormalities to be found in embryos during an assisted reproductive cycle. However, individual factors not linked to the translocation can also produce other chromosome abnormalities (mosaicism, haploidy, polyploidy) and may compromise the chances of achieving a viable pregnancy.     

Chromosomal segregation in spermatozoa of five Robertsonian translocation carriers t(13;14)

Purpose  

To analyse the segregation of a Robertsonian translocation t(13;14) in five male carriers, and to verify a possible inter-chromosomal effect (ICE) of the Robertsonian translocation on chromosomes 18, X, and Y.     

Sperm morphology in subfertile carriers of autosomal translocations.

Sperm morphology of nine translocation carriers was compared with that of subfertile controls with a normal karyotype to determine whether there was a specific morphologic pattern in translocation carriers. The two groups were matched for age, sperm concentration, sperm motility, and presence or absence of a varicocele testis. No specific abnormality of sperm morphology was found among the translocation carriers. No significant difference in either the percentage of abnormal sperm or the morphologic pattern of sperm was observed between the two groups. It was concluded that structural chromosomal aberrations have no relation to sperm morphology.     

Chromosomal segregation in sperm of Robertsonian translocation carriers

Purpose

To study meiotic segregation patterns of Robertsonian translocations in sperm of male carriers and to assess the frequencies of unbalanced sperm formation.

Methods

FISH with combination of probes to detect all the variants of meiotic segregation was performed on decondensed sperm nuclei of 5 carriers of der(13;14), 3 carriers of der(14;21) and one carrier of a rare der(13;21) translocation.

Results

The frequency of sperm with alternate segregation and normal/balanced chromosomal complement ranged from 68 % to 94.4 % (mean 79.2 ± 8.4). Adjacent segregation was detected in 17.9 ± 7.3 % of sperm (from 5.6 % to 29 %). No significant differences in frequencies of gametes with nullisomies and disomies of chromosomes involved in translocations were observed. The mean frequency of 3:0 segregation products was 2.5 ± 1.4 %.

Conclusions

All analyzed patients showed homogenous segregation pattern with clear predominance of alternate segregation resulting in normal/balanced sperm production. Still, from 5.8–32 % (mean 20.4 ± 8.3 %) of sperm was unbalanced, which is the evidence of the increased risk of unbalanced offspring in carriers of Robertsonian translocations. Our results highlight the importance of genetic counseling of Robertsonian translocation carriers prior to ICSI or IVF.     

Risk of reproduction disorders in carriers of mutual chromosomal translocations, and methods for detection of translocation carriers

It is believed that the method of detection of chromosomal translocation carrier state may be a prognostic factor for the risk of giving birth to an ill child with unbalanced karyotype. For verification of this view 30 families were studied which had balanced mutual translocations identified by means of GTG banding technique in the Genetics Laboratory of the Child's Health Centre. In each family the risk was estimated of the development of an undifferentiated karyotype in live born offspring and fetuses in the 2nd trimester of pregnancy using a method evolved by Stengel--Rutkowski et al. (1988). In the group of families identified by examination of a child with abnormalities the individual risk of development of an undifferentiated karyotype in a newborn was from 0.45% to 19.78% and in a fetus it was 4.5% to 46%. In the group of families identified by spontaneous abortion the risk in the newborns was from 0 to 7% and in the fetuses in 2nd trimester it was 0 to 35%, while in the families undergoing cytogenetic examinations for indications other than reproduction disturbances the risk of an unbalanced karyotype in the newborns was from 0 to 23%, and in the fetuses from 0 to 34%. Since in each group of families high-risk translocations were found, the used methods of preliminary estimation of the risk based on the used ways of family identification are open to reservations.     

Quantitative analysis of seminiferous epithelium in subfertile carriers of chromosomal translocations.

In order to study the effect of structural chromosomal aberrations on spermatogenesis, quantitative analysis of the germinal epithelium was performed on testicular specimens from 12 carriers of balanced chromosomal translocations diagnosed at male infertility clinics: a Y-autosome translocation, eight reciprocal translocations, and three D/D Robertsonian translocations. Spermatogenic arrest at the spermatocyte stage was revealed in the Y-autosome translocation and four of the reciprocal translocations. The number of spermatids was selectively reduced in three carriers, while normal spermatogenesis was found in three. Thus, the majority of carriers with impaired semen quality showed a complete or partial reduction in the number of spermatids, suggesting that the effect of chromosomal aberrations is to arrest the spermatogenic process at the spermatocyte stage.     

Analysis of meiotic segregation patterns and interchromosomal effects in sperm from six males with Robertsonian translocations

Purpose To provide more genetic information about meiotic segregation behavior and the possibility of interchromosomal effects (ICE) in spermatozoa from carriers of Robertsonian (Rob) translocations. Materials and methods Meiotic segregation behavior in spermatozoa from six carriers of Rob translocations, four t(13;14), one t(14;22) and one t(13;21), was investigated by dual fluorescence in-situ hybridization (FISH). Aneuploidy for chromosomes 18, X and Y was studied by triple FISH. Results The rate of normal/balanced spermatozoa resulting from alternate segregation ranged from 78.14 to 86.88%. The frequency of unbalanced spermatozoa resulting from adjacent segregation varied between 11.70 and 19.53%. The higher frequencies of aneuploidy for sex chromosome were observed in three Rob translocation carriers. In addition, the increased rates of diploid were found in two t(13;14) carriers. Conclusions Alternate segregation is dominant in the different types of Rob translocations. Some carriers may be at an increased risk for ICE. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. An increased aneuploidy for sex chromosome observed in three Robertsonian translocation carriers suggests that an interchromosomal effect is likely in some carriers.     

Chromosomal translocations and semen quality: A study on 144 male translocation carriers

Research question

Chromosomal translocations are known genetic causes of male infertility. Are certain translocations or chromosomal regions more directly associated with sperm defects? Is there a threshold of sperm impairment that can be relevant for detection of translocations?

Meiotic segregation analysis of embryos from reciprocal translocation carriers in PGD cycles

Meiotic segregation patterns of 278 embryos from 41 preimplantation genetic diagnosis cycles of 34 reciprocal translocation carriers were analysed to investigate whether some characteristics of reciprocal translocation, including terminal breakpoints, acrocentric chromosome or carrier gender, are related to meiotic segregation patterns. The incidence of normal/balanced karyotypes in translocations with terminal breakpoints was significantly lower than those without terminal breakpoints (6.5% versus 14.4%, P = 0.005). The incidences of adjacent-1 (21.0% versus 29.6%), adjacent-2 (16.1% versus 11.1%) and 3:1 (41.9% versus 30.6%) segregation were not statistically significantly different in translocations with terminal breakpoints versus those without. Translocation with acrocentric chromosomes showed a significantly lower rate of 2:2 segregation (39.2% versus 60.2%, P = 0.001) and a higher rate of 3:1 segregation (43.1% versus 27.3%, P = 0.005) than those without acrocentric chromosomes. The incidence of 2:2 segregation was significantly higher in male than in female carriers (58.2% versus 45.0%, P = 0.019). This study suggested that reciprocal translocation involving terminal breakpoints resulted in a lower rate of normal/balanced karyotype in preimplantation embryos. Some characteristics of reciprocal translocation, such as terminal breakpoints, acrocentric chromosome and carrier gender, are related to the segregation patterns.     

Meiotic segregation of a t(7;8)(q11.21;cen) translocation in two carrier brothers

OBJECTIVE: To determine the meiotic segregation of a t(7;8)(q11.21;cen) translocation in two carrier brothers. DESIGN: Analysis of sperm nuclei by fluorescence in situ hybridization (FISH). SETTING: Franche-Comté University Fertility Center in Besan?on, France. PATIENT(S): Two oligospermic brothers with a (7;8) translocation. INTERVENTION(S): Dual FISH for chromosomes 7 and 8, and multicolor FISH for chromosomes X, Y, 15, and 18 were performed. MAIN OUTCOME MEASURE(S): Meiotic segregation differences between both brothers and controls. RESULT(S): In dual FISH 7-8, a total of 34527 (older brother) and 10023 (younger brother) spermatozoa were analyzed. The frequencies of alternate, adjacent 1, adjacent 2, and 3:1 segregations and diploidies were 56.7%, 25.1%, 11.1%, 7.06%, and 0.04%, respectively, in the older brother and 62.84%, 17.61%, 12.8%, 6.47%, and 0.28% in the younger. Also, the disomy rates of some chromosomes not implicated in the translocation would suggest a possible interchromosomal effect. CONCLUSION(S): The similar segregation profiles for the same translocation, compared with those very divergent profiles of the other cases of studied translocations that were published in the literature, confirm that the risks of meiotic imbalances vary primarily according to the characteristics of the chromosomes involved in the rearrangement and the breakpoint position.     

Preferential alternate segregation in the common t(11;22)(q23;q11) reciprocal translocation: sperm FISH analysis in two brothers

Segregation behaviour studies in t(11;22) carriers have reported controversial results. Whereas some authors have detected a preponderance of 3:1 products, no evidence of such prevalence was found by others. This study reports a fluorescence in-situ hybridization (FISH) segregation analysis on decondensed spermatozoa in two brothers, carriers of the same t(11;22)(q23;q11) rearrangement. Data revealed a similar meiotic segregation pattern in both carriers, 2:2 Alternate segregation being the most frequent (42.94 and 45%), while 3:1 genotypes were the least frequent in both patients, with percentages around 10%. The production of three chiasmata, based on the presence of G-light bands along the translocated segments and the presence of recombination sites at 11q and 22q distal regions, are proposed as the cause of a preponderance of the Alternate segregation. Interchromosomal effects involving chromosomes 13, 18, 21, X and Y were also evaluated. An increased frequency of sex chromosome disomies was detected in one patient. Reviewing the literature, a relationship between this phenomenon and the involvement of acrocentric chromosomes in the reorganization is suggested. FISH segregation and interchromosomal effects studies in spermatozoa are encouraged to gather information to establish the best approach for preimplantational genetic diagnosis in reorganization carriers.     

Abnormalities of chromosome involving 1q in uterine endometrial carcinomas

Cytogenetic studies were performed on endometrial specimens from four patients with hyperplasia, six with adenocarcinoma and one with mixed mesodermal tumor. Except for one cell, all 65 cells from the hyperplastic specimens had a normal female karyotype. However, a total of 92 cells from the 5 adenocarcinoma specimens had chromosomal abnormalities, though all 20 cells from a specimen of a well differentiated adenocarcinoma showed a normal karyotype. The chromosome number and morphology of the aneuploid cells had minimal changes. The modal number of chromosomes was pseudodiploid in one case and hyperdiploid in four. Three kinds of structural abnormalities involving chromosomes 1q were identified as of clonal origin: del. 1 (p21) in 2 cases, t. dic (1;16) (p21;q24) in one case and i (1q) markers in 2 cases. Since the carcinoma cells had two chromosomes 1 of normal morphology, the presence of the marker chromosome led to a partial trisomy or tetrasomy of the long arm of a chromosome 1. This involvement of the long arm of chromosome 1, therefore, may be assumed to represent a karyotypic change in the characteristics of adenocarcinoma of the endometrium. Complex karyotypes with many rearranged chromosomes were observed in cells from the mixed mesodermal tumor. The karyotypic differences between endometrial carcinoma and the mixed mesodermal tumor suggest that the genesis (and its mechanism) of the former may differ from that of the latter.     

Preimplantation genetic diagnosis using FISH for carriers of Robertsonian translocations: the Portuguese experience

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis for couples at risk of transmitting genetic disorders to their offspring. We present a fluorescence in situ hybridization (FISH) analysis of embryos obtained after seven PGD cycles in six couples with Robertsonian translocations and male factor infertility: 4 der(13;14), 1 der(14;21) and 1 der(15;21). Of 74 metaphase II (MII) injected oocytes, 61 (82.4%) fertilized normally and cleaved. Of these, 37/61 (60.7%) embryos were of high morphological quality with >or=6 blastomeres. After biopsy of 44 embryos at day 3 of development, seven degenerated, seven arrested in development and 30/44 (68.2%) evolved, of which 25/30 (83.3%) reached the morula/blastocyst stage. Analysis of biopsied blastomeres showed 23/44 (52.3%) of normal/balanced embryos, of which 15 (11 at the morula/blastocyst stage) were transferred in six cycles. One term pregnancy was achieved, which ended by cesarean section at 37 weeks of gestation, giving birth to two healthy newborn. Analysis of 49 embryos (excluding 12 inconclusive cases) showed a predominance of alternate segregation (38/49, 77.6%) over adjacent segregation (7/49, 14.3%), with one (2%) being a polyploid mosaic and three (6.1%) chaotic.     

Mild dysmorphic signs in two male sibs with partial trisomy 2q32.1-->q35 due to maternal ins(14;2) translocation.

We report two male sibs with minor congenital anomalies and moderate to severe developmental delay who are trisomic for the interstitial 2q32.1-->q35 segment. The partial 2q duplication derived from a maternal balanced insertion translocation, 46,XX,dir ins (14;2)(q22;q32.1q35). To the best of our knowledge, no similar case observation has been previously published.     

Prenatal diagnosis of primary anophthalmia with a 3q27 interstitial deletion involving SOX2

We report an interstitial deletion of chromosome 3q26-q28 in a fetus in which anophthalmia had been detected prenatally. FISH analysis, using BAC clones encompassing the SOX2 locus, showed that SOX2 gene was involved in the chromosomal breakpoint of the deletion. This case confirms that haploinsufficiency for SOX2 plays a crucial role in human eye development and emphasizes the necessity of careful chromosomal analysis, including FISH analysis of the 3q region, in case of prenatal discovery of anophthalmia.