Sperm chromosome analysis of two men heterozygous for reciprocal translocations: t(1;9)(q22;q31) and t(16;19)(q11.1;q13.3).

Sperm chromosome complements were analysed in two men who were heterozygous carriers of reciprocal translocations. A total of 363 sperm were karyotyped after in vitro penetration of hamster oocytes, including 180 sperm from a male with a t(1;9)(q22;q31) and 183 from a male with a t(16;19)(q11.1;q13.3). All possible 2:2 and 3:1 meiotic segregations were observed for both translocations. The frequencies of alternate, adjacent 1, adjacent 2, and 3:1 segregations were 46%, 38%, 13%, and 4% for the t(1;9) and 40%, 28%, 31%, and 1% for the t(16;19), respectively. Within the alternate segregation group, the number of normal sperm was not significantly different from the number of sperm carrying a balanced form of the translocation for either of the translocations, as expected. There was no evidence for an interchromosomal effect of either translocation, since the frequencies of numerical abnormalities unrelated to the translocation were within the normal range observed in sperm from control donors. The percentage of sperm with an unbalanced form of the translocation was 54% for the t(1;9) and 61% for the t(16;19).     

Predisposition for breast cancer in carriers of constitutional translocation 11q;22q.

A translocation between the long arms of chromosomes 11 and 22, t(11;22)(q23;q11), is the most frequent constitutional reciprocal translocation in man. This chromosome abnormality has not previously been reported to be associated with an increased risk for neoplasia. The observation of one patient with a constitutional translocation t(11q;22q) and breast cancer prompted us to study the relationship between these two conditions. The incidence of breast cancer was determined in carriers of t(11q;22q). The karyotypes were determined by QFQ-banding, and the breakpoints were then further characterized by fluorescent in situ hybridization. Eight families with a total of 22 balanced carriers were found. In five of these families there was one case of breast cancer each. In another family a case of an unknown malignancy was reported in one member. No other malignancies were found among these patients. The number of breast cancer cases was significantly higher than expected among the translocation carriers (P < .001). The chromosomal breakpoints showed the same localization with the markers used, in the seven families studied. The association of constitutional translocation t(11q;22q) and breast cancer identifies a subset of patients with a highly increased risk for breast cancer who would benefit from counseling and screening. It also suggests the involvement of genes on 11q and/or 22q, in the tumorigenesis of breast cancer.     

Unusual chromosomal mosaicism as a cause of mental retardation and congenital malformations in a familial reciprocal translocation carrier, t(17;22)(q24.2;q11.23)

Familial reciprocal translocations are generally without phenotypic effect, although there is some evidence for a small excess of mental retardation and congenital malformations (MR/CM) in children carrying familial reciprocal translocations. Possible mechanisms whereby such translocations could have a phenotypic effect include cryptic unbalanced rearrangements, uniparental disomy, and disruption of putative genes at the breakpoints, unmasking recessive alleles on the normal homologs. Mosaicism for a supernumerary derivative chromosome in a carrier of a familial reciprocal translocation has not yet been described. We report a boy presenting with MR/CM and a familial reciprocal translocation, t(17;22)(q24.2;q11.23), inherited from the mother. Cytogenetic analysis of peripheral blood lymphocytes showed a balanced karyotype in all 32 analyzed metaphase spreads. Molecular genetic analysis was consistent with biparental origin of the normal homologs. In metaphase spreads from skin fibroblasts a supernumerary chromosome was found in all 24 cells analyzed and could be identified as der(22)t(17;22)(q24.2;q11.23). Several possible segregation modes at meiosis I followed by meiosis II or postzygotic nondisjunction of the der(22) might have led to this unusual chromosomal mosaicism. We propose hidden mosaicism as a possible cause for MR/CM in patients who apparently carry a balanced familial reciprocal translocation.     

The 11q;22q translocation: A European collaborative analysis of 43 cases

Summary Translocation between the long arms of chromosomes 11 and 22 is usually detected in offspring with an unbalanced karyotype following a 3:1 disjunction resulting in partial trisomy. Since by the end of 1976 it was suspected that this translocation might be more frequent than one would deduce from published reports, it was decided to call for a collaborative effort in Europe to collect unpublished cases. In response, 42 cases were collected in Europe, and one case from New Zealand was added. The following countries were represented with the number of cases indicated in parentheses: Czechoslovakia (2), Denmark (4), Finland (3), France (6), Germany (1), Italy (5), The Netherlands (9), Sweden (6), United Kingdom (4), Yugoslavia (2). The wide geographical distribution indicates a multifocal origin of the translocation. Among the unpublished cases, 31 were ascertained as unbalanced carriers [47,XX or XY,+der(22),t(11;22)] and 12 as balanced balanced carriers [46,XX and XY,t(11;22)]. Among the published cases, 10 were ascertained in unbalanced and 3 in balanced carriers. The breakpoints of the translocations indicated by the contributors varied, the most frequently reported being 11q23;22q11 (25 cases), followed by q25;q13 (10 cases). While the first one seems more likely, it was not possible to decide whether the breakpoints were the same in all cases.All 32 probands with unbalanced karyotypes had inherited the translocation, 31 from the mother and only 1 from the father. This ratio became 43:1 when the published cases were added. A segregation analysis revealed that in families ascertained through probands with unbalanced karyotypes there was a ratio of carriers to normal (all karyotyped) 54:55, not a significant difference. The formal maximum (minimum) recurrence risk for this unbalanced translocation was calculated to be 5.6% (2.7%). When the ascertainment was through a balanced proband, the maximum risk was 2.7%. The risk was calculated as 5.7% for female and 4.3% for male carriers. The mean family size was 1.67 for the offspring of female carriers and 0.78 for the offspring of male carriers. This significant difference suggests that heterozygosity for the translocation reduces fertility in males. Indeed, several of the probands with balanced karyotypes were ascertained because of sub- or infertility. Only 2 de novo translocations were found among the 59 probands, and both, were among the 12 cases ascertained as balanced carriers. The source, quality, and quantity of the clinical data for the subjects with unbalanced karyotypes were variable, and no definite conclusions were possible about phenotypes. The following signs were recorded in 10 or more of the 45 cases: low birth weight, delayed psychomotor development, hypotonia, microcephaly, craniofacial asymmetry, malformed ears with pits and tags, cleft palate, micro-/retrognathia, large beaked nose, strabismus, congenital heart disease, cryptorchidism, and congenital dislocation of the hip joints. Many signs were similar to those considered typical of trisomy 11q, and the phenotype coincided almost completely with the presumptive phenotype of complete trisomy 22. No cases with coloboma was recorded, while other signs of the cat-eye syndrome were found in several probands. This might indicate that individuals with the cat-eye syndrome and carriers of the unbalanced 11/22 translocation have the same segment of 22 in triplicate plus or minus another chromosome segment.     

Interchange trisomy 21 by t(1;21)(p22;q22)mat

Interchange trisomy 21 by t(1:21)(p22:q22)mat: Interchange trisomy 21 by t(1;21)(p22;q22)mat was identified in a sporadic patient with Down syndrome. With a 21q22 specific probe, we observed signals on both normal 21 chromosomes and on the der. We reviewed the 23 published reports of families with reciprocal translocations leading to viable offspring with interchange trisomy 21. The breakpoints in chromosome 21 were mainly located in 21q (19/24 instances, including the present report) and in 19/23 cases the other chromosome involved in the translocation was (pairs 1-12). The underlying 3:1 segregation occurred mainly in carrier mothers; only one patient presented a de novo imbalance and in another case the father was the carrier. In addition, there were 4 instances of concurrence with another unbalanced segregation (adjacent-1 or tertiary trisomy) and 3 families with recurrence of interchange trisomy 21. The mean age of 14 female carriers at birth of interchange trisomy 21 offspring (24.8 yr) was lower that the mean (28.3 yr) found in a larger sample of mothers of unbalanced offspring due to 3:1 segregation (mostly tertiary trisomics) and was not increased with respect to the general population average. Overall, these data agree with previous estimates regarding recurrence risk (9-15%) and abortion rate (about 28%) in female carriers ascertained through an interchange trisomic 21 child.     

Homologous Robertsonian translocation (21q21q) and abortions

Summary Instances of balanced Robertsonian translocations between the homologues of chromosome 21 were observed in two couples with a history of repeated abortions. The male partner of one couple and the female partner of another couple exhibited this anomaly. The translocation (21q21q) was found to be transmitted to their live children with Down's syndrome.     

De novo microdeletion on an inherited Robertsonian translocation chromosome: a cause for dysmorphism in the apparently balanced translocation carrier.

Robertsonian translocations are usually ascertained through abnormal children, making proposed phenotypic effects of apparently balanced translocations difficult to study in an unbiased way. From molecular genetic studies, though, some apparently balanced rearrangements are now known to be associated with phenotypic abnormalities resulting from uniparental disomy. Molecular explanations for other cases in which abnormality is seen in a balanced translocation carrier are being sought. In the present paper, an infant is described who has retarded growth, developmental delay, gross muscular hypotonia, slender habitus, frontal bossing, micrognathia, hooked nose, abundant wispy hair, and blue sclerae. Cytogenetically, she appeared to be a carrier of a balanced, paternally derived 14;21 Robertsonian translocation. Analysis of DNA polymorphisms showed that she had no paternal allele at the D14S13 locus (14q32). Study of additional DNA markers within 14q32 revealed that her previously undescribed phenotype results from an interstitial microdeletion within 14q32. Fluorescent in situ hybridization was used to show that this microdeletion had occurred de novo on the Robertsonian translocation chromosome. These observations may reactivate old suspicions of a causal association between Robertsonian translocations and de novo rearrangements in offspring; a systematic search for similar subcytogenetic rearrangements in other families, in which there are phenotypically abnormal children with apparently balanced translocations, may be fruitful. The clinical and molecular genetic data presented also define a new contiguous gene syndrome due to interstitial 14q32 deletion.     

A Palindrome-Mediated Recurrent Translocation with 3:1 Meiotic Nondisjunction: The t(8;22)(q24.13;q11.21)

Palindrome-mediated genomic instability has been associated with chromosomal translocations, including the recurrent t(11;22)(q23;q11). We report a syndrome characterized by extremity anomalies, mild dysmorphia, and intellectual impairment caused by 3:1 meiotic segregation of a previously unrecognized recurrent palindrome-mediated rearrangement, the t(8;22)(q24.13;q11.21). There are at least ten prior reports of this translocation, and nearly identical PATRR8 and PATRR22 breakpoints were validated in several of these published cases. PCR analysis of sperm DNA from healthy males indicates that the t(8;22) arises de novo during gametogenesis in some, but not all, individuals. Furthermore, demonstration that de novo PATRR8-to-PATRR11 translocations occur in sperm suggests that palindrome-mediated translocation is a universal mechanism producing chromosomal rearrangements.     

A second nonrandom translocation, der(16)t(1;16)(q21;q13), in Ewing sarcoma and peripheral neuroectodermal tumor

The majority of Ewing sarcomas and peripheral neuroectodermal tumors (PNET) that have been karyotyped contain a specific translocation, t(11;22)(q23;q11). We report here a second nonrandom translocation, der(16)t(1;16)(q21;q13), in 2 of 20 cases of Ewing sarcoma (seven previously unreported) and 2 of 7 cases of PNET (all previously unreported). All cases with this translocation also contained the t(11;22). Comparison of C-banding patterns in tumor and peripheral lymphocyte karyotypes in one case indicated that the likely breakpoints were 1q21 and 16q13. The presence of this translocation in cell lines will enable further investigation of the molecular events important in the pathogenesis of Ewing sarcoma and PNET.     

Meiotic studies of a human male carrier of the common translocation, t(11;22), suggests postzygotic selection rather than preferential 3:1 MI segregation as the cause of liveborn offspring with an unbalanced translocation

The t(11;22)(q23;q11) translocation is the only non-Robertsonian rearrangement for which there are a large number of unrelated families, apparently with the same breakpoints. These families most often have been ascertained through an abnormal child with the karyotype 47,XX or XY, +der(22) t(11;22)(q23;q11). To explain the high incidence of 3:1 segregants, rarely seen in offspring of carriers of other reciprocal translocations, a number of theoretical models have been suggested. We have used both electron microscope analysis of the synaptonemal complex (SC) and dual-color FISH to investigate the meiotic chromosome behavior in a male carrier of the translocation who has the karyotype 46,XY, t(11;22)(q23;q11). Chromosome synapsis, first-meiotic chiasma configuration, and segregation behavior of this translocation have been analyzed directly. Examination of SCs by electron microscopy showed pachytene-cross formation in 49/50 nuclei. Approximately 50% (26/50) revealed a classical fully synapsed quadrivalent. A proportion of these (10/26), however, showed some central asymmetry, suggesting heterologous synapsis. The remaining cells appeared to have incomplete synapsis. FISH analysis showed only quadrivalents in all 100 metaphase I nuclei. The chiasma frequency was increased within the interstitial segments, in comparison with the same region in normal bivalents. All types of segregation category were found in metaphase II nuclei. There was no indication of preferential 3:1 anaphase I segregation. We conclude that the +der(22) constitution in offspring of carriers of t(11;22)(q23;q11) is not likely to be due to meiotic 3:1 segregation being especially common. Rather, the +der(22) constitution is more likely to be the result of postzygotic selection against other unbalanced karyotypes.     

A new centric fusion translocation in cattle: rob (13;19)

A new Robertsonian translocation has been found in cattle. A bull from Marchigiana breed (central Italy) was found to be a heterozygous carrier of a centric fusion translocation involving cattle chromosomes 13 and 19 according to RBA-banding and cattle standard nomenclatures. CBC-banding revealed the dicentric nature of this new translocation, underlining the recent origin of this fusion. In fact, both the bull's parents and relatives had normal karyotypes. In vitro fertilization tests were also performed in the bull carrying the new translocation, in two bulls with normal karyotypes (control) and in four other bulls carrying four different translocations.     

Multicolor fluorescence in situ hybridization analysis of the spermatozoa of a male heterozygous for a reciprocal translocation t(11;22)(q23;q11)

A reciprocal translocation between chromosomes 11 and 22 is a site-specific translocation that has been seen in many families with no common ancestry. This translocation is of particular interest because balanced carriers have a 0.7–3.7% risk of having children with the supernumerary der(22), resulting from a 3:1 segregation. We have used a three color fluorescence in situ hybridization (FISH) with specific DNA probes to determine the chromosome segregation pattern of a male carrier of a translocation t(11;22)(q23;q11). The probes selected included a centromeric marker for chromosome 11, a marker closely linked to the centromere of chromosome 22, and a third probe distal to the translocation breakpoint of chromosome 22. The results showed that 3 : 1 segregation is preferential in this patient, with 40.1% of spermatozoa belonging to this segregation type. Alternate segregation followed with 27.4% of analyzed spermatozoa; 17.6% resulted from adjacent 1 and 12.5% resulted from adjacent 2 segregation. We detected 0.5% of presumably diploid spermatozoa. Complementary adjacent 1 products were observed at statistically different frequencies (P = 0.02). Complementary adjacent 2 products without recombination in the interstitial segments were also seen at different frequencies (P = 0.002). In 3 : 1 segregation, the products containing one chromosome were observed more frequently than those with three chromosomes (P = 0.0001). The 24,+der(22) gamete was seen more frequently than all of the other gametes combined which had 24 chromosomes resulting from 3 : 1 segregation. The results of this study demonstrate that in this t(11;22) carrier, 3 : 1 segregation is preferential but not exclusive. Received: 9 December 1998 / Accepted: 1 March 1999     

Autosomal dominant congenital cataract and microphthalmia associated with a familial t(2;16) translocation

Summary We describe a family in which autosomal dominant congenital cataract and microphthalmia were segregating together with a reciprocal translocation t(2; 16) (p22.3;p13.3) through three generations. This family included four individuals with balanced translocations, three with partial trisomy 2p derived from this translocation, and two with a normal karyotype. All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the two individuals with normal karyotypes did not show any ocular anomalies. These observations suggest that the altered function of a gene that lies on the 16p13.3 band and that has an important role in the development of the eye is responsible for this disorder.     

Transmission of a t(13q22q) chromosome observed in three generations with segregation of the translocation D1-trisomy syndrome.

A case of an inherited type of D/G translocation D1-trisomy syndrome was described. A female proposita who had the clinical signs of D1-trisomy syndrome was found to have a chromosome complement of 46,XX,--G,+t(DqGq). examination of Q- and G-stained karyotypes revealed that the chromosomes involved in the translocation were members of Nos. 13 and 22, or t(13q22q) with breaks at p12 of both chromosomes. C-stained figures also showed a large heterochromatin block in its centromeric region. The t(13q22q) chromosome was transmitted from the paternal grandmother of the proposita through at least three generations.     

Translocation (13q21q)

Summary A (13q21q) translocation was found in an infant with Down's syndrome. The 17-year-old mother and the grandmother carried the translocation 45,XX,t(13;21)(p12;q11). The great grandparents had normal karyotypes. Fluorescence marker studies suggested that the translocation originated in the great grandmother. The hypothesis was supported by satellite association studies which showed a significant excess of 13–21 and 13–15 associations in the great grandmother.     

A complex chromosomal rearrangement with a translocation 4;10;14 in a fertile male carrier: ascertainment through an offspring with partial trisomy 14q13-->q24.1 and partial monosomy 4q27-->q28 [corrected

Complex chromosomal rearrangements (CCRs) are usually associated with infertility or subfertility in male carriers. If fertility is maintained, there is a high risk of abnormal pregnancy outcome. Few male carriers have been identified by children presenting with mental retardation/congenital malformations (MR/CM) or by spontaneous abortions of the spouses. We report a de novo CCR with five breakpoints involving chromosomes 4, 10 and 14 in a male carrier who was ascertained through a son presenting with MR/CM due to an unbalanced karyotype with partial trisomy 14 and partial monosomy 4. The child has a healthy elder brother. In the family history no abortions were reported. No fertility treatment was necessary. Cytogenetic analysis from the affected son showed a reciprocal translocation t(4;10) with additional chromosomal material inserted between the translocation junctions in the derivative chromosome 10. The father showed the same derivative chromosome 10 but had additionally one aberrant chromosome 14. Further molecular cytogenetic analyses determined the inserted material in the aberrant chromosome 10 as derived from chromosome 14 and revealed a small translocation with material of chromosome 4 inserted into the derivative chromosome 14. Thus the phenotype of the son is supposed to be associated with a partial duplication 14q13-->q24.1 and a partial monosomy 4q27-->q28. Including our case we are aware of eleven CCR cases with fertile male carriers. In eight of these families normal offspring have been reported. We propose that exceptional CCRs in fertile male carriers might form comparatively simple pachytene configurations increasing the chance of healthy offspring.     

Familial translocation t(10;21)(q22;q22)

Summary A family is described with a translocation t(10;21)(q22;q22) transmitted through three generations. This family was studied for the apparition of several miscarriages and two sisters with multiple malformations. Both children had a probably partial trisomy of chromosome 10 and a monosomy of chromosome 21 due to a maternal adjacent-2 meiotic segregation.     

A family with a high risk of segregation for an autosomal unbalanced reciprocal translocation

Summary A family with autosomal reciprocal translocation t(4;13) (q25;q31) with a sibship comprising 2 children with unbalanced karyotypes, der(13) partial trisomy 4q, 1 child with the balanced translocation, and 2 abortions were studied. The segregation risk of unbalanced derivation in reciprocal translocations is discussed. The clinical picture of the 2 children with partial trisomy 4q is compared with similar cases.     

Analysis of segregation and aneuploidy in two reciprocal translocation carriers, t(3;9)(q26.2;q32) and t(3;9)(p25;q32), by triple-color fluorescence in situ hybridization

Meiotic segregation patterns of chromosomes 3 and 9 were analyzed in sperm of two translocation carriers (t(3;9)(q26.2;q32) and t(3;9)(p25;q32)) by triple-color fluorescent in situ hybridization (FISH) with a telomeric DNA probe in addition to two centromeric probes. The frequencies of each sperm product resulting from alternate or adjacent I, adjacent II and 3:1 segregation in a t(3;9)(q26.2;q32) translocation carrier were 88.35%, 5.44% and 5.94%, respectively. On the other hand, the frequencies of each sperm product in a t(3;9)(p25;q32) translocation carrier were 89.23%, 6.02% and 4.48%, respectively. Of all the sperm products, the frequency of normal or chromosomally balanced sperm in a t(3;9)(q26.2;q32) and a t(3;9)(p25;q32) were 52.49% and 47.25%, respectively. The frequencies of each sperm product resulting from various segregations were different between both carriers and significantly deviated from the expected frequencies. Additional dual-color and triple-color FISH were performed to analyze aneuploidy rates for chromosomes 12, 17, 18, X and Y in order to detect any interchromosomal effect; no evidence of an interchromosomal effect was found.     

Embryonic loss in superovulated cattle caused by the 1;29 Robertsonian translocation

The effect of the 1;29 Robertsonian translocation on fertility was studied using embryos resulting from matings of nine carrier cows and two carrier bulls. Embryos were collected from the following three mating groups utilizing superovulation: normal bull cross normal cow, normal bull cross translocation carrier cow, and translocation carrier bull cross normal cow. The proportion of ova which were fertilized did not vary among the groups, indicating that fertilization rates were not affected by the translocation. The translocation cows did yield fewer embryos on average than did cows with normal karyotypes, which may suggest ovulation rates are reduced (at least after superovulation attempts) in cattle carrying the 1;29 translocation. Twenty of 39 embryos successfully karyotyped had abnormal chromosome complements. All four of the theoretically predicted karyotypes and two additional abnormal combinations were found. Eight of 39 (20.5%) embryos karyotyped had unbalanced karyotypes which would have resulted in embryonic loss. The proportion of embryos with unbalanced karyotypes, was slightly higher when the cow (36%) carried the translocation than when the bull (19%) did. Results of this study indicate that fertility is impaired due to the presence of this translocation. The major loss in reproductive potential appears to be due to embryonic loss rather than fertilization failure.