Transmission ratio distortion in offspring of heterozygous female carriers of Robertsonian translocations

Robertsonian translocations are the most common structural rearrangements of human chromosomes. Although segregation of Robertsonian chromosomes has been examined in many families, there is little consensus on whether inheritance in the balanced progeny conforms to Mendelian ratios. To address this question, we have compiled previously reported segregation data, by sex of parent, for 677 balanced offspring of Robertsonian carriers from 82 informative families and from a prenatal diagnosis study on the risk of unbalanced offspring in carriers of chromosome rearrangements. Care was taken to avoid any source of ascertainment bias. Our analysis supports the following conclusions: (1) the transmission ratio is not independent of the sex of the carrier; (2) the transmission ratio distortion is observed consistently only among the offspring of carrier females; (3) the transmission ratio distortion does not appear to be dependent on the presence of a specific acrocentric chromosome in the rearrangement. The sex-of-parent-specific origin of the non-Mendelian inheritance, the finding that the rearranged ("mutant") chromosomes are recovered at significantly higher frequency than the acrocentric ("normal") chromosomes, and the similarities between these observations and the segregation of analogous rearrangements through female meiosis in other vertebrates strongly support the hypothesis that the transmission ratio distortion in favor of Robertsonian translocations in the human results from the preferential segregation of chromosomes during the first meiotic division. This non-Mendelian inheritance will result in increased overall risk of aneuploidies in the families of Robertsonian translocation carriers, independently of the origin of the transmission ratio distortion.     

Two sibs with duplication of 4q31-->qter due to 3:1 meiotic disjunction and mild phenotype

Two sibs with duplication of 4q31-->qter due to 3:1 meiotic disjunction and mild phenotype: Clinical and cytogenetic findings in two sibs with partial duplication of 4q31.3-->qter and 21q11.2-->pter are reported. These patients are rare cases of reoccurrence of those partial trisomies due to 3:1 segregation of a maternal balanced translocation. A review of the literature reporting cases of trisomy of the 4q31-->qter segment is also made; previously reported cases mostly in addition have deletions of other chromosomes resulting from adjacent segregation of balanced translocation. The findings of our study confirm the high risk for offspring with unbalanced rearrangements in women with reciprocal translocation involving acrocentric and short chromosome segments. The study also points out that duplication of 4q31-->qter may go along with only mild phenotypic findings if there is no significant additional aneuploidy of the other chromosome involved in the rearrangement.     

Cryptic Subtelomeric Rearrangements and X Chromosome Mosaicism: A Study of 565 Apparently Normal Individuals with Fluorescent In Situ Hybridization

Five percent of patients with unexplained mental retardation have been attributed to cryptic unbalanced subtelomeric rearrangements. Half of these affected individuals have inherited the rearrangement from a parent who is a carrier for a balanced translocation. However, the frequency of carriers for cryptic balanced translocations is unknown. To determine this frequency, 565 phenotypically normal unrelated individuals were examined for balanced subtelomeric rearrangements using Fluorescent In Situ hybridization (FISH) probes for all subtelomere regions. While no balanced subtelomeric rearrangements were identified, three females in this study were determined to be mosaic for the X chromosome. Mosaicism for XXX cell lines were observed in the lymphocyte cultures of 3 in 379 women (0.8%), which is a higher frequency than the 1 in 1000 (0.1%) reported for sex chromosome aneuploidies. Our findings suggest that numerical abnormalities of the X chromosome are more common in females than previously reported. Based on a review of the literature, the incidence of cryptic translocation carriers is estimated to be approximately 1/8,000, more than ten-fold higher than the frequency of visible reciprocal translocations.     

Embryos of Robertsonian Translocation Carriers Exhibit a Mitotic Interchromosomal Effect That Enhances Genetic Instability during Early Development

Balanced chromosomal rearrangements represent one of the most common forms of genetic abnormality affecting approximately 1 in every 500 (0.2%) individuals. Difficulties processing the abnormal chromosomes during meiosis lead to an elevated risk of chromosomally abnormal gametes, resulting in high rates of miscarriage and/or children with congenital abnormalities. It has also been suggested that the presence of chromosome rearrangements may also cause an increase in aneuploidy affecting structurally normal chromosomes, due to disruption of chromosome alignment on the spindle or disturbance of other factors related to meiotic chromosome segregation. The existence of such a phenomenon (an inter-chromosomal effect—ICE) remains controversial, with different studies presenting contradictory data. The current investigation aimed to demonstrate conclusively whether an ICE truly exists. For this purpose a comprehensive chromosome screening technique, optimized for analysis of minute amounts of tissue, was applied to a unique collection of samples consisting of 283 oocytes and early embryos derived from 44 patients carrying chromosome rearrangements. A further 5,078 oocytes and embryos, derived from chromosomally normal individuals of identical age, provided a robust control group for comparative analysis. A highly significant (P = 0.0002) increase in the rate of malsegregation affecting structurally normal chromosomes was observed in association with Robertsonian translocations. Surprisingly, the ICE was clearly detected in early embryos from female carriers, but not in oocytes, indicating the possibility of mitotic rather than the previously suggested meiotic origin. These findings have implications for our understanding of genetic stability during preimplantation development and are of clinical relevance for patients carrying a Robertsonian translocation. The results are also pertinent to other situations when cellular mechanisms for maintaining genetic fidelity are relaxed and chromosome rearrangements are present (e.g. in tumors displaying chromosomal instability).     

Report of large kinship with familial translocation between chromosomes 21 and 22.

This paper reports a large kinship with a familial (21;22) translocation occurring in both the balanced and the unbalanced states. Recurrence risks for the (21;22) translocation in the unbalanced state are high (14%) for the offspring of female carriers as compared with those for the offspring of male carriers (4%), but the offspring of male carriers appear to have a much higher risk (50%) of being balanced carriers than those of female carriers (30%).     

No evidence for a paternal interchromosomal effect from analysis of the origin of nondisjunction in Down syndrome patients with concomitant familial chromosome rearrangements.

The parental origin of the extra chromosome 21 was determined with DNA polymorphisms in seven families in whom the proband and one of the parents carried an additional chromosome rearrangement (balanced translocation or pericentric inversion) not involving chromosome 21. The balanced rearrangement was inherited from the mother in two families and from the father in five families, whereas the additional chromosome 21 was derived from the mother in all seven families. These findings are not in agreement with the hypothesis of a paternal interchromosomal effect. The latter would imply that a balanced rearrangement in the father would favor nondisjunction during meiosis in the germ cells.     

The frequency of chromosome abnormalities in farm animals and their economic consequences

Examinations during the last two decades of the chromosome complements of various species of domestic animals have revealed the existence of a considerable number of abnormalities, including inherited rearrangements: approximately 20 in cattle, 15 in pigs (predominantly reciprocal translocations), 3 in sheep, 2 in horses (predominantly monosomy X), and 1 in goats. (The accumulation of data on the frequency of such abnormalities and evaluation of their effects on reproductive performances of carriers of inherited rearrangement depends on a number of factors including the use of artificial insemination, number or progeny per sire or dam, and differences in generation intervals of the species concerned). The economic value of the cytogenetic findings depends on the degree of exchange of information between the breeders and the cytogenetics laboratories. An example of a successful collaboration is a Swedish study of a centric fusion translocation in Swedish Red and White cattle, one that affects chromosomes 1 and 29. There, the fertility-reducing effects of the translocation led to a loss of approximately $250,000. Recognition of the significance of the translocation prompted a search for carrier bulls and their elimination from the artificial insemination units. In swine, in which artificial insemination is used much less than in cattle, data on the frequency of reciprocal translocations in general must be obtained from the farms themselves. The main effect of an inherited chromosome rearrangement is a reduction in the number of offspring, perhaps to 50%, i.e., five piglets per litter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Paracentric inversion of chromosome 14 plus rare 9p variant in a couple with habitual spontaneous abortion.

A couple presenting with habitual spontaneous abortion both showed a chromosome rearrangement. The male had an apparently balanced paracentric inversion of chromosome 14 - 46,XY,inv(14) (q11q32). The female had a karyotype with a rare large short arm variant of chromosome 9 - 46,XX,var(9) (p11p21). Testing of a living normal child showed that he had inherited both rearrangements. Family testing showed the chromosome 9 variant in three generations, with all carriers being of normal phenotype and intelligence. This study confirms that the presence of more than one chromosomal rearrangement can be compatible with normal development. This is useful for genetic counselling. Nevertheless when such cases arise, each must be individually assessed.     

Inv21p12q22del21q22 and intellectual disability

Chromosomal rearrangements are common in humans. Pericentric inversions are among the most frequent aberrations (1–2%). Most inversions are balanced and do not cause problems in carriers unless one of the breakpoints disrupts important functional genes, has near submicroscopic copy number variants or hosts “cryptic” complex chromosomal rearrangements. Pericentric inversions can lead to imbalance in offspring. Less than 3% of Down syndrome patients have duplication as a result of parental pericentric inversion of chromosome 21. We report a family with an apparently balanced pericentric inversion of chromosome 21. The proband, a 23-year-old female was referred for prenatal diagnosis at 16 weeks gestation because of increased nuchal translucency. She has a familial history of Down's syndrome and moderate intellectual disability, a personal history of four spontaneous abortions and learning difficulties. Peripheral blood and amniotic fluid samples were collected to perform proband's and fetus' cytogenetic analyses. Additionally, another six family members were evaluated and cytogenetic analysis was performed. Complementary FISH and MLPA studies were carried out. An apparent balanced chromosome 21 pericentric inversion was observed in four family members, two revealed a recombinant chromosome 21 with partial trisomy, and one a full trisomy 21 with an inverted chromosome 21. Array CGH analysis was performed in the mother and the brother's proband. MLPA and aCGH studies identified a deletion of about 1.7 Mb on the long arm of inverted chromosome 21q22.11. We believe the cause of the intellectual disability/learning difficulties observed in the members with the inversion is related to this deletion. The recombinant chromosome 21 has a partial trisomy including the DSCR with no deletion. The risk for carriers of having a child with multiple malformations/intellectual disability is about 30% depending on whether and how this rearrangement interferes with meiosis.     

Mutation rates of structural chromosome rearrangements in man.

The gametic mutation rates of human structural chromosome rearrangements have been estimated from rearrangements ascertained from systematic surveys of live births and spontaneous abortions. The mutation rates for rearrangements that survive long enough to give rise to clinically recognized pregnancies are 2.20 X 10(-4) for balanced rearrangements, 3.54 X 10(-4) for unbalanced Robertsonian translocations, and 3.42 X 10(-4) for unbalanced non-Robertsonian rearrangements. These estimates give a mutation rate for all detectable structural chromosome rearrangements of approximately 1 X 10(-3). The most common single rearrangement, the Robertsonian translocation involving chromosomes 13 and 14, has a mutation rate of 1.5 X 10(-4).     

Is sperm FISH analysis still useful for Robertsonian translocations? Meiotic analysis for 23 patients and review of the literature

Background

Robertsonian translocations (RobT) are common structural chromosome rearrangements where carriers display a majority of chromosomally balanced spermatozoa from alternate segregation mode. According to some monotony observed in the rates of balanced segregation, is sperm FISH analysis obsolete for RobT carriers?

Methods

Retrospective cohort research study on 23 patients analyzed in our center from 2003 to 2017 and compared to the data of 187 patients in literature from 1983 to 2017.Robertsonian translocation carriers were divided in six groups according to the chromosomes involved in the translocation: 9 patients from our center and 107 from literature carrying 45,XY,der(13;14) karyotype, 3 and 35 patients respectively with 45,XY,der(14;21), 5 and 11 patients respectively with 45,XY,der(13;15), 4 and 7 patients respectively with 45,XY,der(14;15), 1 and 4 patients respectively with 45,XY,der(13;22),and 1 and 10 patients respectively with 45,XY,der(14;22).

Results

Alternate segregation mode is predominant in our group of Robertsonian translocation carriers with 73.45% ±8.05 of balanced spermatozoa (min 50.92%; max 89.99%). These results are compliant with the data from literature for all translocations types (p?>?0.05) and are consistent among the different types of Robertsonian translocations (p?>?0.05) except for der(13;15) that exhibit lower balanced spermatozoa rates (p?<?0.05 versus der(13;14), der(14;21), (13;21) and der(15;22)). Normozoospermic patients also display a significantly (p?<?0.01) higher rate of balanced sperm cells than patients with abnormal seminograms whatever the defect implied.

Conclusions

According to the discrepancies observed between der(13;15) and all the other Rob T carriers, the differences observed among patients presenting normal and abnormal sperm parameters and the input in genetical counselling, sperm FISH does not seem obsolete for these patients. Moreover, it seems important to collect more data for rare RobT.

     

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.     

Mating between two balanced translocation carriers in two unrelated families

Partial trisomy 9p and a 13/14 translocation occurred in the daughter of a t(5;9)(p15;p12) mother and a t(13;14)(p11;q11) father. Two additional offspring displayed a normal karyotype and a translocation trisomy 13 respectively. Two first cousins, selected for chromosome analysis because of a spontaneous abortion, were found to have an identical translocation t(14;21)(p11;q11). Their second pregnancy was monitored by midtrimester amniocentesis and disclosed a balanced fetus. The different zygotic chromosome constitutions and the counselling problems in the marriages between two balanced translocation carriers are discussed.     

Inheritance of a translocation between chromosomes 12 and 16 in a family with recurrent miscarriages and a newborn with Down syndrome carrying the same translocation

Reciprocal translocation carriers have reduced fertility, increased risk of spontaneous abortion or unbalanced karyotype in their offspring. Here, we report the inheritance of a translocation between chromosomes 12 and 16 in a family with recurrent miscarriages and a newborn with Down syndrome carrying the same translocation. Chromosomal analysis from fetal amniotic fluid and peripheral blood lymphocytes from the family were performed at the Cukurova university hospital in Turkey. We assessed a family in which the translocation between chromosomes 12 and 16 segregates; one of the eight progenies with the karyotype 47,XY,+21,t(12;16)(q24;q24) was heterozygote for the translocation and presented with Down syndrome. His mother is phenotypically normal, one brother and one sister were also carrying the same translocation. Apparently, this rearrangement occurred due to the unbalanced chromosome segregation of the mother [t(12;16)(q24;q24)mat]. This case will enable us to explain the behavior of segregation patterns and the mechanism for each type oftranslocation from carrier to carrier and their effects on reproduction and numerical aberrations. The t(12;16) is also associated with fetal wastage and may play a role in the etiology of the family's miscarriages. These findings can be used in clinical genetics and may be used as an effective tool for reproductive guidance and genetic counseling.     

Inherited structural cytogenetic abnormalities detected incidentally in fetuses diagnosed prenatally: frequency, parental-age associations, sex-ratio trends, and comparisons with rates of mutants

Rates of structural chromosome abnormalities were analyzed in 24,951 fetuses studied prenatally in which there were no grounds to suspect an inherited abnormality. In about one in 200 prenatal cytogenetic diagnoses, an unexpected structural abnormality was found. The observed rate was 5.3 per 1,000, of which 1.7 per 1,000 were unbalanced and 3.6 per 1,000 balanced. The rate of inherited abnormalities was 3.1-3.7 per 1,000 (0.4-0.9 per 1,000 for unbalanced abnormalities and 2.6-2.8 per 1,000 for balanced abnormalities). The rate of mutants in this series was, by contrast, 1.6-2.2 per 1,000 (0.8-1.2 per 1,000 for unbalanced abnormalities and 0.8-1.0 per 1,000 for balanced abnormalities). The rate of balanced Robertsonian translocation carriers was 0.6 per 1,000 (about 0.25 per 1,000 for mutants and 0.35 per 1,000 for inherited abnormalities), and for other balanced abnormalities, 3.0 per 1,000 (about 0.6 per 1,000 for mutants and 2.4 per 1,000 for inherited abnormalities). The rates of unbalanced Robertsonian translocations was about 0.1 per 1,000, almost all of which were mutants. For supernumerary rearrangements, the rate was 0.9 per 1,000 (about 0.4 per 1,000 inherited and 0.5 per 1,000 mutant). The rates of all unbalanced (nonmosaic) inherited abnormalities (4.0-5.2 per 10,000) were intermediate between higher rates estimated in all conceptuses (9.1-15.8 per 10,000) and rates observed in newborns (1.5-2.5 per 10,000). This trend is probably attributable to fetal mortality associated with unbalanced rearrangements. The rates of balanced (nonmosaic) inherited abnormalities (26.0-28.0 per 10,000), however, were considerably higher than the rates in all conceptuses (13-16.7 per 10,000) or in all live births (12.2-16.0 per 10,000). The major difference was in the rate of inversions. The use of "banding" methods in the studies of amniocentesis but not in most of the live births or abortus studies probably contributes to at least some of these differences. One trend in parental age among the inherited abnormalities was noteworthy. Paternal age was elevated for inherited balanced reciprocal structural abnormalities of paternal origin but not of maternal origin. With regard to sex ratio, there was a greater proportion of females than males among the unbalanced rearrangements both inherited and mutant. There was no obvious sex difference among the balanced rearrangements.     

Sperm analysis in a subfertile male with a Y;16 translocation, using four-color FISH.

Sperm analysis was performed in a male with oligoasthenoteratozoospermia (OAT) and a reciprocal t(Y;16) (q11. 21;q24), using four-color FISH. Intracytoplasmic sperm injection (ICSI) treatment in this patient had resulted in the birth of one chromosomally balanced and two chromosomally normal children. To assess the risk of having a chromosomally unbalanced conception after ICSI, morphologically normal spermatozoa were studied with a set of probes allowing detection of all segregation variants. There were 51% normal or balanced sperm cells. The fraction of sperm products resulting from alternate and adjacent I segregation was 87%, 12% were products of 3:1 disjunction, and the other 1% had other types of aneuploidy. If morphologically abnormal cells were also included in the FISH analysis, nearly 90% of all the spermatozoa were unbalanced. We conclude that although the majority of males with a Y/autosome translocation are infertile due to azoospermia, our patient produces sufficient morphologically and chromosomally normal spermatozoa to have chromosomally normal or balanced offspring after ICSI. Assuming that ICSI with an unbalanced spermatozoon from this patient would result in a nonviable embryo in many cases, the combination of in vitro and subsequent in vivo selection probably results in a risk of unbalanced offspring of much less than 50%. Hence, FISH studies on the sperm of translocation carriers are useful for estimating the risk of having unbalanced offspring after ICSI and in understanding the mechanisms underlying infertility in such carriers.     

Chromosome Segregation Analysis in Human Embryos Obtained from Couples Involving Male Carriers of Reciprocal or Robertsonian Translocation

The objective of this study was to investigate the frequency and type of chromosome segregation patterns in cleavage stage embryos obtained from male carriers of Robertsonian (ROB) and reciprocal (REC) translocations undergoing preimplantation genetic diagnosis (PGD) at our reproductive center. We used FISH to analyze chromosome segregation in 308 day 3 cleavage stage embryos obtained from 26 patients. The percentage of embryos consistent with normal or balanced segregation (55.1% vs. 27.1%) and clinical pregnancy (62.5% vs. 19.2%) rates were higher in ROB than the REC translocation carriers. Involvement of non-acrocentric chromosome(s) or terminal breakpoint(s) in reciprocal translocations was associated with an increase in the percent of embryos consistent with adjacent 1 but with a decrease in 3∶1 segregation. Similar results were obtained in the analysis of nontransferred embryos donated for research. 3∶1 segregation was the most frequent segregation type in both day 3 (31%) and spare (35%) embryos obtained from carriers of t(11;22)(q23;q11), the only non-random REC with the same breakpoint reported in a large number of unrelated families mainly identified by the birth of a child with derivative chromosome 22. These results suggest that chromosome segregation patterns in day 3 and nontransferred embryos obtained from male translocation carriers vary with the type of translocation and involvement of acrocentric chromosome(s) or terminal breakpoint(s). These results should be helpful in estimating reproductive success in translocation carriers undergoing PGD.     

A rare case of aniridia and balanced translocation (5;11) (p15.3;q22) arising in the same subject: a challenge for genetic counseling

The authors report on a case of isolated aniridia caused by haploinsufficiency of the PAX6 gene, which is located on 11p13, and a balanced translocation t(5;l1)(p15.3;q22) inherited respectively from his father and his mother. Due to the coincidence of two abnormalities in the same chromosome, the segregation of the mutant allele leading to aniridia and of the chromosomes involved in the translocation are not independent events. Considering that both monosomy and trisomy for 11q22-qter are unviable, his offspring may inherit either the PAX6 mutation or the balanced translocation. However, depending on the occurrence of crossing over, there is a possibility for him to have normal offspring; on the other hand, he may also father children with both anomalies. This unusual case, in which the proband has a presumably very low chance of completely normal offspring, turned to be a challenge for genetic counseling.     

Chiasma distributions and chromosome segregation in male and female translocation heterozygous mice analysed using FISH

Two factors postulated to influence the meiotic behaviour of reciprocal translocations were investigated. Firstly, variation in the length of translocated and non-translocated segments was studied in male mice using four different rearrangements involving chromosomes 2 and 4. Secondly, sex-related effects were analysed through comparison of the meiotic behaviour of two translocations in male and female germ cells. In the first part of the study, primary and secondary spermatocytes of male mice carrying a translocation [T(2;4)1Ca, T(2;4)13H, T(2;4)1Sn, or T(2;4)1Go] were screened. Each rearrangement had different proportions of cells with ring and chain quadrivalents at metaphase I; the T(2;4)1Sn heterozygote also had a high rate (45%) of translocation bivalents. In general, the translocations had elevated chiasma frequencies in the rearranged chromosomes compared with structurally normal chromosomes 2 and 4, although the extent of the effect varied. Each rearrangement produced a different array of segregation products at metaphase II, reflecting their contrasting frequencies of multivalent configurations at metaphase I. Comparison of chromosome behaviour at metaphase I and II suggested that certain configurations tended to adopt particular orientations. However, it was also clear that such correlations were imprecise and that other factors, possibly the exact positions of chiasmata, also played a role in multivalent orientation. Two rearrangements, T(2;4)1Go and T(7;16)67H, were analysed in female mice. The frequencies of the various multivalent types at metaphase I differed from those in male carriers of these rearrangements owing to an increased chiasma frequency in oocytes in some of the pairing segments. Not surprisingly, the segregation products seen in metaphase II cells showed some differences from the pattern recorded in male germ cells. For T(2;4)1Go, the sex-related difference in segregation patterns resulted in a diminished expectation of genetically imbalanced gametes, although this was not the case for T(7;16)67H. Received: 6 June 1998 / Accepted: 9 October 1998     

A jumping Robertsonian translocation: a molecular and cytogenetic study

We report a patient with mosaicism for two different Robertsonian translocations, both involving chromosome 21. She carries an unbalanced cell line with an i(21q) and a balanced cell line with a rob(21q22q). She is phenotypically normal but has two children who inherited the i(21q) and have Down syndrome. We demonstrate that both abnormal chromosomes are dicentric and that the proband’s 21/21 rearrangement is an isochromosome formed from a maternally derived chromosome 21. We propose a model in which the i(21q) is the progenitor rearrangement in the proband, which subsequently participated in a nonreciprocal rearrangement characteristic of a jumping translocation. In addition, we review other cases of constitutional mosaicism involving jumping translocations. Received: 4 October 1995 / Revised: 14 February 1996