A novel family-specific translocation t(2;20)(p24.1;q13.1) associated with recurrent abortions: molecular characterization and segregation analysis in male meiosis

In the present study, we present a novel reciprocal translocation t(2;20)(p24.1;q13.1) and its segregation in a three generation family. The rate of miscarriages (50%) in pregnancies from male translocation carriers could be explained by unbalanced translocation-bearing spermatozoa found with a frequency of approximately 55% in the entire sperm population of a t(2;20)(p24.1;q13.1) carrier. These imbalanced spermatozoa mainly present as 2, der(20) and der(2), 20 missegregated (approximately 46%) while adjacent 2 and 3:1 segregation patterns account for approximately 5% and 4% of imbalances, respectively. While the translocation is associated clearly with an increased risk of early abortions (7/12) in both male and female carriers, no malformed livebirths were observed. Our results suggest complete embryonic lethality of imbalanced offspring. With respect to a high rate of segregation to 2, der(20) and to der(2), 20 imbalanced spermatozoa in male translocation carriers and with respect to known cases of partial trisomy 2p and 20q we consider that their corresponding monosomies result in fetal loss. This is the first study reporting multiple abortions associated with partial monosomy 20q13.1-->qter and 2pter-->p24.1 and the first report on the frequency of chromosomal imbalances in gametes of a male t(2;20)(p24.1;q13.1) heterozygote.     

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.     

Cytogenetic and histologic analyses of spontaneous abortions

Summary In a study of spontaneous abortions the correlations between karyotype (166 cases), anamnestic data, and macroscopic and histologic findings in placentas (107 cases) and embryos (73 cases) were analyzed. The main results were: 1. The rate of chromosomal aberrations was 39%. Trisomies predominated (60%), followed by monosomy X (20%), triploidies (14%), and structural aberrations (6%). 2. In trisomies a clear prevalence of female sex constitution (2:1) was observed. In normal karyotypes a slight prevalence of females was seen (1.2:1). 3. With increasing maternal age, more trisomies were found in the abortions. 4. Women whose index abortion had a normal karyotype had a history of fewer births but more abortions. 5. Trisomies of acrocentric chromosomes were mainly chorionic sacs with an embryo, while trisomies of the other autosomes resulted in intact empty sacs. 6. The average developmental stage of the embryos was 5 weeks, with a mean gestational age of 14 weeks. Gross malformations were found in 58% of the embryos.     

A rare reciprocal translocation (12;21) segregating for nine generations

An autosomal reciprocal translocation (12;21) was found in five seemingly unrelated families in Finland. Three families had had multiple spontaneous abortions and two families had a child with Down's syndrome. The genealogies of the five families were traced using population registries, and four families were found to have a common ancestor born in 1752. Kinship to the fifth family could not be established but its ancestors were traced back to the same rural parishes as those of the four other families. The translocation segregated at the same frequency as normal chromosomes. A statistically insignificant increase in spontaneous abortions was detected when the matings of translocation carriers were compared with non-carrier matings. The increase may however be clinically significant. These results permit more accurate counselling in these and similar translocation families.     

Four familial translocations ascertained through spontaneous abortions

Summary In a study of 514 spontaneous abortions, 194 were found to have a chromosome anomaly. Of these, 4 (2.1%) were unbalanced translocations. Three of the translocations were Robertsonian (13q14q) and one was reciprocal. Each translocation was ascertained independently and each was associated with a balanced rearrangement in a carrier parent.     

Excess of mental retardation and/or congenital malformation in reciprocal translocations in man

Summary In this report the Leuven experience (1970–1984) on reciprocal translocations is summarized. A total of 153 unrelated index patients, carriers of different types of reciprocal translocations, and their families were investigated. Familial reciprocal, apparently balanced translocations were found in 75 unrelated families bringing the total numbers of translocation carrier parents and their offspring to 132 and 445, respectively. In 61.5% of the patients the reciprocal translocation was detected after the birth of a malformed child with unbalanced karyotype or through investigation because of recurrent spontaneous abortions, stillbirths, or infertility. In 41 patients (28 familial and 13 de novo), however, the reciprocal balanced translocation was found to be associated with mental retardation and/or congenital malformations (MR/CM) which is significantly higher than expected. This excess of MR/CM in de novo and familial balanced translocation carriers is illustrated and discussed.     

Analysis of translocations observed in three different populations. I. Reciprocal translocations

A sample of 437 reciprocal translocations was classified into three groups according to their method of ascertainment (Group I = couples with repeated abortions; Group II = karyotypically unbalanced carriers; Group III = balanced translocation heterozygotes). Statistical analysis showed that the distributions of chromosome breaks observed in the three groups could not be accounted for by chromosome arm length alone. In couples with repeated abortions, an excess of breaks in 7p, 17p, and 22q was found, whereas in the balanced translocation heterozygotes an excess of breaks was found only in 11q. An excess of breaks was found in arms 9p, 14p, 18p, 18q, 21q, and 22q in karyotypically unbalanced probands. A significant decrease of breaks in the medial chromosome regions was accompanied by a concomitant increase in the terminal regions in all groups. The three groups demonstrated different distributions of chromosome arm involvement in the observed translocations. Balanced translocation heterozygotes had the highest frequency of large (greater than the length of 4p) translocated segments and an excess in the frequency of large-large translocations, whereas karyotypically unbalanced probands had the highest frequency of small (shorter than 21q) translocations and an excess in the frequency of small-small translocations. For each type of chromosomal imbalance observed, the balanced translocation heterozygotes demonstrated the greatest potential imbalance and the karyotypically unbalanced probands the least.     

A prevalent Y;15 translocation in the Ethiopian Beta Israel community in Israel

We describe 7 cases of abnormal karyotypes involving chromosomes Y and 15 in Ethiopian Beta Israel patients: 46,XX, der(15)t(Y;15)(q12;p12) and 46,XY,der(15)t(Y;15)(q12;p12). Six cases were incidentally found in amniocentesis performed for various indications; the indication for karyotyping in 1 case was recurrent abortions. To the best of our knowledge, this is the first report of this translocation in a specific ethnic group. We conclude that the derivative chromosome 15 with chromosome Y is probably a normal variant in Ethiopian Beta Israel occurring at an estimated frequency of 4/74 (5.4%). The prenatal diagnosis of this translocation in this population probably does not require further parental testing.     

First trimester abortions associated with a translocation t(1;20)(p36;p11)

Summary A large family with a high rate of spontaneous abortions was found also to have a high incidence of a reciprocal translocation.     

罗伯逊易位分子机理初探

目的：探讨复发性自然流产与染色体罗伯逊易位间的关系。方法：采用人外周血淋巴细胞培养,常规G显带技术行染色体核型检查,并结合临床资料对其进行分析。结果：57对复发性自然流产夫妇中,检出罗伯逊易位染色体核型4例,检出率3.51%。结论：罗伯逊易位是导致复发性流产的重要原因之一,对复发性自然流产患者进行常规的染色体检查及遗传咨询具有一定的临床意义。     

Possible risk factors for Down syndrome and sex chromosomal aneuploidy in Mysore, South India

BACKGROUND:

Down syndrome (DS) and sex chromosomal aneuploidy (SA) are common chromosomal anomalies causing congenital malformations and mental retardation in humans. The well-established risk factor, advanced maternal age, was not found in many of the DS and SA cases in India, while the other possible risk factors have not been well studied. In view of this, the present study has been made.

MATERIALS AND METHODS:

During the last 5 years, 150 clinically suspected DS and 25 SA cases were referred to our laboratory for chromosome investigation from major hospitals of Mysore city. Chromosome preparations were made from these patients after informed consent was obtained. Well-spread G-banded metaphase plates were analyzed by automated LEICA KARYO software. Two hundred and 100 randomly selected families belonging to different religions were used as controls for the DS and SA cases, respectively. Statistical analysis was carried out using logistic regression

RESULTS:

Out of the 150 cases of DS, 122 had free trisomy 21, two were mosaic trisomy 21, and one had translocation. Logistic regression of case-control study of DS children revealed that the odds ratio of uncle-niece marriages, or second cousin marriages, or parents lived in rural region, or exposure of the parents to chemicals, or parents education status, or habits (tobacco/ alcohol used) of father, or mother not undergone prenatal scanning, or mothers with previous abortions were significant when all the variables of that category were used one at a time. Exposure of the parents to chemicals, parents’ educational status, habits (tobacco/alcohol use) of the father, mother not undergone prenatal scanning, and history of previous abortions were significant when all the variables of that category were used one at a time. Similarly, except for consanguinity, history of previous abortions, and mother not undergone prenatal scanning, all other factors showed significant odds ratios in SA cases.

CONCLUSION:

Besides the known risk factors, consanguinity, region (rural/urban) of residence of parents, exposure of parents to chemicals, educational status of parents, habits of father, prenatal scanning, and reproductive performance of mother are possible risk factors for chromosomal aneuploidy.     

Chromosome translocations: study of 232 cases originating from 144 families

Between 1974 and 1987, 232 translocation carriers have been detected in our Center; they belong to 144 different families. Indications for chromosome analysis were the following: familial studies in relation with a patient suggesting a chromosome anomaly (25.4%); mental retardation with or without malformations (24.6%); 2 or more spontaneous abortions (17.2%); infertility problems, mainly male (16.4%); genetic counseling for a non-chromosomal disease (9.5%); prenatal diagnosis in risk pregnancies (6.9%). The chromosome anomalies detected were the following; balanced Robertsonian fusions (114 cases = 49.1%); balanced translocations (74 cases = 31.9%); unbalanced translocations, Robertsonian fusions included (44 cases = 19%). Two groups may be distinguished: the first one confirms data already known, such as high frequency of balanced translocations in couples with multiple abortions, or in infertile males. The second group on the contrary shows more unusual observations: 4 cases of standard trisomy 21 born to young parents carriers of a balanced translocation not involving chromosome 21; 5 cases of trisomy 13 with 46 chromosomes and a Robertsonian fusion, born to parents carriers of a t(13q; Dq) (twice the mother and thrice the father); 14 cases of apparently balanced translocations, however with an abnormal phenotype; and finally 22 cases of balanced translocations incidentally detected during the course of investigations in patients with a genetic problem generally not associated with a chromosome defect.     

The segregation of a translocation t(1;4) in two male carriers heterozygous for the translocation

Summary We examined the meiotic segregation pattern of a t(1;4)(p36.2;q31.3) reciprocal translocation in two male cousins heterozygous for the translocation. The wife of subject 1 had four recognized spontaneous abortions and two carrier daughters, and the wife of subject 2 had three recognized spontaneous abortions and no liveborn children. The results showed that subject 1 had an imbalance rate of 54% and subject 2 had an imbalance rate of 61% with respect to the translocation. This was not statistically different (P = 0.3174) and the 95% confidence intervals overlapped for each segregation type. The sex ratio of X- and Y-bearing sperm was not statistically different than the expected 50%. The rate of structural abnormalities was 11.3% in subject 1 and 17.8% in subject 2. Both of these values were above the range of control subjects in our lab, but only subject 2's value fell outside the 95% confidence interval for the control population.     

A cytogenetic study of repeated spontaneous abortions.

During a cytogenetic study of spontaneous abortions, successive abortions from 40 couples were karyotyped. The chromosome constitutions of the first and second abortions were found to be highly correlated. In each of 21 instances in which the first abortion was chromosomally normal, the subsequent abortion(s) was normal as well. In nine cases, the two abortions were chromosomally abnormal, and in four of these, both abortions were trisomic. Combined with findings from other studies of consecutive spontaneous abortions, the present data indicate that certain couples are at an increased risk for either repeated chromosomally normal abortions or for repeated trisomic conceptions. The increased risk of trisomy does not seem to be restricted to a particular chromosome, and the magnitude of the risk increase appears to be independent of maternal age.     

Cytogenetics and mechanisms of spontaneous abortions: increased apoptosis and decreased cell proliferation in chromosomally abnormal villi

Genetic defects of the zygote, such as chromosome aberrations, are the most frequent causes of abnormal embryonic development and spontaneous abortion. However, the underlying mechanisms remain unknown. Chromosome aberrations likely cause changes in placental morphology and function (such as size, shape, vascularity, and the presence of trophoblastic inclusion). We postulated that chromosome aberrations may affect rates of cell proliferation or programmed cell death (apoptosis) during the differentiation of chorionic villi. To address these questions, we evaluated cell proliferation using a monoclonal antibody to Ki-67 (a cell-cycle marker) and apoptosis using the in situ end-labeling method (TUNEL) on paraffin-embedded placental tissues. Tissues were obtained from spontaneous abortions in early gestational periods with normal (11 cases) and abnormal karyotypes (15 cases), as well as eight normal control placentas from elective abortions. Apoptotic cells were found in the stroma of all cases, but were significantly higher in number in the stroma of chromosomally abnormal versus chromosomally normal spontaneous abortions. The apoptotic index of the trophoblasts was not significantly different between groups. Cell proliferation was higher in muscularized blood vessels in chromosomally normal placentas (both elective and spontaneous abortions) versus chromosomally abnormal spontaneous abortions. Cell proliferation was different in the trophoblast and stroma between the groups but to a lesser degree than in blood vessels. The morphological and biological data presented here suggest that: (1) chromosomally abnormal spontaneous abortions may occur because of different mechanisms than chromosomally normal spontaneous abortions, (2) apoptosis of the stromal cells and cell proliferation in blood vessels and stroma play an important role in the differentiation and functioning of villi, and (3) these changes could explain the etiology of spontaneous abortion and growth retardation of chromosomally abnormal embryos.     

Recombination in a balanced complex translocation of a mother leading to a balanced reciprocal translocation in the child. Review of 60 cases of balanced complex translocations

We report an unusual case of a balanced reciprocal translocation with a recombinant chromosome which has arisen from a familial balanced complex translocation. Fluorescence in situ hybridization studies were essential for the identification of the breakpoints. A review of 60 cases of balanced complex translocations (BCT) has revealed three cases similar to ours. Carriers of BCT have a high risk of having spontaneous abortions or a child with an unbalanced karyotype. Certain types of balanced rearrangements involving an insertion can give rise to a simpler balanced translocation as a result of crossover. Our observations support the assumption that the chance that a de novo balanced complex translocation is associated with an abnormal phenotype increases with the number of breakpoints. Received: 27 March 1996 / Revised: 28 January 1997     

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.     

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.     

Use of linkage disequilibrium data in prenatal diagnosis of cystic fibrosis

Summary The authors report a case of 11;17 translocation associated with recurrent spontaneous abortions, and request contact with colleagues who have observed similar cases.     

Analysis of chromosome segregation during preimplantation genetic diagnosis in both male and female translocation heterozygotes

Individuals carrying translocations suffer from reduced fertility or spontaneous abortions and seek help in form of assisted reproductive technology (ART) and preimplantation genetic diagnosis (PGD). While most translocations are relatively easy to detect in metaphase cells, the majority of embryonic cells biopsied in the course of in vitro fertilization (IVF) procedures are in interphase. These nuclei are thus unsuitable for analysis by chromosome banding or painting using fluorescence in situ hybridization (FISH). Thus several methods have been devised to detect translocation imbalance through FISH in single cells for purpose of PGD, among them polar body chromosome painting, interphase FISH with combination of subtelomeric and centromeric probes, breakpoint spanning probes, and cell conversion. Results with PGD indicate a significant decrease in spontaneous abortions, from 81% before PGD to 13% after PGD. They also indicate very high rates of chromosome abnormalities in embryos from translocation carriers, 72% for Robertsonian translocations and 82% for reciprocal translocations. Sperm analysis was found to be a good predictor of IVF and PGD outcome, with samples with more than 60% abnormal forms indicating poor prognosis. Similarly, the predictability from first PGD cycle results for future cycles was 90%. In summary, PGD can help translocation carriers to achieve viable pregnancies, but the success of the process is conversely related to the baseline of unbalanced gametes.