Risk estimates for balanced reciprocal translocation carriers — prenatal diagnosis experience

An analysis was performed on 40 families at risk for an unbalanced rearrangement in the fetus because one of the parents is a reciprocal translocation carrier. The overall risk at second trimester prenatal diagnosis was 14% (8/57). The individual risks for unbalanced offspring at second trimester prenatal diagnoses and at birth were estimated using empirical data by Stengel-Rutkowski et al. (1988). The risks at birth ranged from 0%–21.6%. Most reciprocal translocations (22 or 55%) were at low risk. Without risk (7 or 17.5%), medium risk (6 or 15%) and high risk (5 or 12.5%) translocations were about equally represented and relatively infrequent. The analysis shows that the mode of ascertainment as well as the measurement of lengths of observed or probable imbalances cannot serve as a reliable risk predictor in individual counselling. In the translocations ascertained through spontaneous abortions the risk is frequently small or nonexistent, but remarkable exceptions to this rule are observed. Translocations discovered through unbalanced offspring were found to belong to different risk groups with the exception of the no risk group. Individual risk estimates have to be performed as a basis of genetic counselling before or during pregnancy so that parents with reciprocal translocations can make their choices regarding the available options.     

Genetic counseling in carriers of reciprocal chromosomal translocations involving long arm of chromosome 16

Families with balanced chromosomal changes ascertained by unbalanced progeny, miscarriages, or by chance are interested in their probability for unbalanced offspring and other unfavorable pregnancy outcomes. This is usually done based on the original data published by Stengel-Rutkowski et al. several decades ago. That data set has never been updated. It is particularly true for the subgroup with low number of observations, to which belong reciprocal chromosomal translocations (RCTs) with breakpoint in an interstitial segment of 16q. The 11 pedigrees from original data together with the new 18 pedigrees of RCT carriers at risk of single-segment imbalance detected among 100 pedigrees of RCT carriers with breakpoint position at 16q were used for re-evaluation of the probability estimation for unbalanced offspring at birth and at second trimester of prenatal diagnosis, published in 1988. The new probability rate for unbalanced offspring after 2 : 2 disjunction and adjacent-1 segregation for the total group of pedigrees was 4 +/- 3.9% (1/25). In addition, the probability estimate for unbalanced fetuses at second trimester of prenatal diagnosis was calculated as 2/11, i.e. 18.2 +/- 11.6%. The probability rates for miscarriages and stillbirths/early deaths were about 16 +/- 7.3% (4/25) and <2% (0/25), respectively. Considering different segment lengths of 16q, higher probability rate (0/8, i.e. <6.1%) for maternal RCT carriers at risk of distal 16q segment imbalance (shorter segment) was obtained in comparison with the rate (0/10, i.e. <4.8%) for RCT at risk of proximal segment imbalance (longer segment). It supports findings obtained from the original data for RCT with other chromosomes, where the probability for unbalanced offspring generally increased with decreasing length of the segments involved in RCT. Our results were applied for five new families with RCT involving 16q, namely three at risk of single-segment imbalance [t(8;16)(q24.3;q22)GTG, ish(wcp8+,wcp16+;wcp8-,wcp16+), t(11;16)(q25;q22)GTG, and t(11;16)(q25;q13)GTG] and two with RCT at risk of double-segment imbalance [t(16;19)(q13;q13.3)GTG, isht(16;19)(q13;q13.3) (D16Z3+,16QTEL013-D19S238E+,TEL19pR-; D16Z3-, D19S238E-,TEL19pR+), and t(16;20)(q11.1;q12)GTG, m ish,t(16;20)(wcp16+,wcp20+;wcp16+,wcp20+)]. They have been presented in details to illustrate how the available empiric data could be used in practice for genetic counseling.     

河南地区586例染色体相互易位的热点断裂区域分析

目的分析河南地区人群染色体相互易位的发生率、常见易位的染色体和核型以及断裂区域,并探讨不同断裂区域对河南地区人群妊娠史或发育史的影响。方法对2016年2月至2018年4月因不孕不育、自然流产、反复流产、死胎等不良妊娠史或发育异常到郑州大学第一附属医院遗传与产前诊断中心遗传咨询和检查的62477例患者进行外周血淋巴细胞染色体核型分析,对染色体相互易位的发生率、常见相互易位的染色体和核型以及断裂区域进行统计。结果62477受检者中共检测出586例染色体相互易位携带者,发生率为0.94%。染色体相互易位群体中,572例染色体相互易位携带者为不孕症患者,发生率为0.92%,14例为发育异常患者,发生率为0.02%。染色体累及次数显示,1号、4号、7号和11号相互易位染色体累及次数最多;核型t(11;22)(q25;q13)累及次数最多。断裂区域分析显示,相互易位染色体共累及出现437个断裂区域,其中11q23、22q13和1p36累及次数最多,且引起携带者不孕不育、流产、胚胎停止发育、先天畸形、发育迟缓/智力低下或表型正常等。结论河南地区染色体相互易位不孕症携带者的发生率为0.92%。断裂区域分析结果表明相互易位累及的染色体及其断裂区域对携带者的妊娠或发育存在影响。探讨相互易位染色体的断裂区域能为携带者提供准确的遗传、生殖和发育咨询,也为阐述断裂区域附近基因功能和寻找新基因及其作用机制提供参考依据。     

Three cases of mosaicism for balanced reciprocal translocations

Mosaicism for a balanced reciprocal translocation (BRTM) is rare. As far as we know only 26 cases of BRTM, demonstrated in lymphocyte cultures, have been described, five of which had an abnormal phenotype. Prenatally three confirmed cases with a normal phenotypic outcome have been described. Here we present three further cases of BRTM in lymphocyte cultures. The first was detected during a family study, the second after an abnormal karyotype in chorionic villus sampling, and the third because of a history of stillborn children. All three carriers have normal phenotypes. An inventory of the BRTM cases reported so far is made. Am. J. Med. Genet. 79:362–365, 1998. © 1998 Wiley-Liss, Inc.     

Pregnancy outcome in carriers of Robertsonian translocations

Robertsonian translocation carriers are at increased risk for infertility, spontaneous abortions, or chromosomally unbalanced offspring. Reproductive counseling of these carriers is challenging. We performed a retrospective analysis of all prenatal diagnoses from Robertsonian translocation carriers during the time period January 1, 1992 through December 31, 2007. Data on the carriers and the results of their prenatal analyses were retrieved as well as data on their previous pregnancies. We identified 28 female and 20 male carriers of Robertsonian translocations and results on 79 prenatal samples were obtained. Among female carriers, 10.3% of chorionic villus sampling and 5.9% of amniocentesis results were unbalanced, whereas for male carriers, this was 3.6% and 0%, respectively. When considering all pregnancies involving carriers, 52.7% of those to female carriers and 61.8% of those to male carriers led to the birth of a healthy child. Male carriers in whom the translocation was ascertained because of infertility or recurrent miscarriages appear to be at higher risk, whereas carriers in whom ascertainment was because of a family history are at lower risk. We conclude that pregnancies of Robertsonian translocation carriers are at increased risk for chromosomal imbalance, and prenatal chromosomal testing should be discussed. More than half of the pregnancies led to the birth of a healthy child, but prediction of which couples will be successful in obtaining a pregnancy with or without assisted reproductive technologies and/or embryo selection remains difficult. The reason for ascertainment of the translocation should be taken into account when counseling these couples. The possibility of preimplantation genetic diagnosis should also be discussed with the couples.     

精子荧光原位杂交分析男性染色体相互易位携带者的减数分裂分离

目的探讨用精子荧光原位杂交（fluorescence in situ hybridization，HSH）分析男性染色体相互易位携带者减数分裂的分离。方法对4例男性染色体相互易位携带者的精子通过化学方法解聚，在2条易位染色体的断裂点两侧的4个染色体区域中分别选用位于其中3个区域的3个位点探针，进行多色FISH，分析精子染色体组成并推断其分离类型。结果4例染色体相互易位携带者的核型分别为46，XY，t（2；18）（p16；q23）、46，XY，t（4；6）（q34；q21）、46，XY，t（8；13）（q23；q21）和46，XY，t（4；5）（4q31；5q13），其分离结果是：对位分离精子占27．1％～49．4％，邻位-1分离精子占26．9％～37．6％，邻位-2精子占2．7％～15．7％，3：1分离精子占8．6％～33．7％，减数分裂Ⅱ不分离精子占0．2％～1．9％，4：0或二倍体精子占0．1％～0．4％。结论不同的男性染色体相互易位携带者减数分裂的分离结果可能不同，对其行精子FISH分析有助于提供更准确的遗传咨询和行胚胎植入前遗传学诊断的预后估计。     

Familial additional chromosomal fragment ascertained in amniotic cell culture

A case with a prenatally diagnosed, additional metacentric chromosomal fragment is reported. Investigation of other family members showed that the fragment must be present in at least three generations. The pregnancy was continued and a healthy girl was born.     

Detection of subtle reciprocal translocations by fluorescence in situ hybridization

Three different subtle reciprocal translocations were detected on long, well-banded chromosomes. The same translocations were examined using fluorescence in situ hybridization (FISH) with chromosome-specific libraries and unique DNA sequences. Our findings show that FISH allows rapid and unequivocal detection and characterization of this type of chromosome rearrangement. This approach is especially useful for prenatal diagnosis when one of the parents is a balanced carrier of such small fragment translocations.     

Factors influencing maternal estimates of genetic risk

The relationship between the objective and subjective estimates of genetic risk was studied in 202 women accepting and 50 women not accepting amniocentesis. All women were at risk of having a child with congenital anomalies either because of maternal age at pregnancy or family history of Down syndrome (DS) or other congenital anomalies. Only 28.6% of the women rejecting and 44.4% of the women accepting amniocentesis remembered correctly their objective odds. The correlations between the objective risk estimates and the subjective risk estimates were low overall (r = 0.089, p = 0.08); for women rejecting (r = 0.024, p = 0.44) or accepting (r = 0.082, p = 0.12) amniocentesis. The psychosocial and sociodemographic variables relating to either objective or subjective risk estimates were different for both groups of women. The study provides information on variables that should be taken into consideration in formulating a general theory to predict individual perceptions of genetic risk.     

Balanced reciprocal translocations: risk factors for aneuploid segregant viability

Reciprocal translocations were studied in two groups of balanced carrier couples: 202 had 210 translocation aneuploid between (LB) infants, and 95 couples had repetitive abortions (AB) without liveborn aneuploids. The observed translocation aneuploidies in the LB group were compared to predicted potential aneuploidies in AB by frequency of chromosome involvement, meiotic segregation mode, and mean trisomic, monosomic and combined genomic imbalances. Qualitative and quantitative differences identified genomic regions and chromosomes possibly vital for in utero survivability. LB aneuploidies indicate non-random chromosome involvement, selection of least detrimental segregants and segments, and predominant transmission from maternal balanced carriers (especially in 3:1 tertiary segregation, 93.5%). For an individual with a balanced reciprocal translocation and untested reproductive capability, an approach is given for predicting whether a translocation aneuploid conceptus will be liveborn or aborted.     

Partners with reciprocal translocations: genetic counseling for the 'double translocation'

SV at age 2 years presented with multiple congenital anomalies including an absent left kidney, anal stenosis, vertebral abnormalities, partial sacral agenesis, microcephaly, dysmorphic facial features, growth deficiency, and developmental delay. She was found to have a complex chromosomal rearrangement derived from balanced translocations in each parent.     

Preimplantation genetic diagnosis in female and male carriers of reciprocal translocations: clinical outcome until delivery of 312 cycles

Carriers of reciprocal translocations (rcp) are known to be at risk for reproductive difficulties. Preimplantation genetic diagnosis (PGD) is one of the options these carriers have to try in order to fulfil their desire to have a child. In the present study, we retrospectively looked at the results of 11 years (1997-2007) of PGD for rcp in our center to improve the reproductive counseling of these carriers. During this period 312 cycles were performed for 69 male and 73 female carriers. The mean female age was 32.8 years, the mean male age 35.8 years. Most carriers were diagnosed with a translocation because of fertility problems or recurrent miscarriages, and most of them opted for PGD to avoid these problems. In 150 of the 312 cycles, embryo transfer (ET) was feasible and 40 women had a successful singleton or twin pregnancy. This gives a live birth delivery rate of 12.8% per started cycle and of 26.7% per cycle with ET. Owing to the large number of abnormal embryos, PGD cycles for rcp often lead to cancellation of ET, explaining the low success rate when expressed per cycle with oocyte pick-up. Once ET was feasible, the live birth delivery rate was similar to that of PGD in general at our center. PGD is therefore an established option for specific reciprocal translocation carriers.     

High resolution banding of an unusual reciprocal translocation in recurrent abortions

Reciprocal translocations involving two chromosomes frequently cause abortion of unbalanced offspring. In many cases, however, meiosis leads to a cytogenetically normal or balanced gamete with normal embryonal development. In a couple investigated because of recurrent reproductive loss, the husband had a reciprocal exchange of parts of the long arms of chromosomes 9 and 10 in the form of inverted insertions. Due to difficulties in obtaining regular homologous pairing during zygotene, this anomaly might not be compatible with cytogenetically normal or balanced offspring. The diagnosis of this translocation was possible using a previously published alkaline Giemsa G-banding technique.     

Clinical application of whole‐genome low‐coverage next‐generation sequencing to detect and characterize balanced chromosomal translocations

Individuals carrying balanced translocations have a high risk of birth defects, recurrent spontaneous abortions and infertility. Thus, the detection and characterization of balanced translocations is important to reveal the genetic background of the carriers and to provide proper genetic counseling. Next‐generation sequencing (NGS), which has great advantages over other methods such as karyotyping and fluorescence in situ hybridization (FISH), has been used to detect disease‐associated breakpoints. Herein, to evaluate the application of this technology to detect balanced translocations in the clinic, we performed a parental study for prenatal cases with unbalanced translocations. Eight candidate families with potential balanced translocations were investigated using two strategies in parallel, low‐coverage whole‐genome sequencing (WGS) followed‐up by Sanger sequencing and G‐banding karyotype coupled with FISH. G‐banding analysis revealed three balanced translocations, and FISH detected two cryptic submicroscopic balanced translocations. Consistently, WGS detected five balanced translocations and mapped all the breakpoints by Sanger sequencing. Analysis of the breakpoints revealed that six genes were disrupted in the four apparently healthy carriers. In summary, our result suggested low‐coverage WGS can detect balanced translocations reliably and can map breakpoints precisely compared with conventional procedures. WGS may replace cytogenetic methods in the diagnosis of balanced translocation carriers in the clinic.     

Benefits and drawbacks of preimplantation genetic diagnosis (PGD) for reciprocal translocations: lessons from a prospective cohort study

Preimplantation genetic diagnosis (PGD) using fluorescence in situ hybridisation probes was carried out for 59 couples carrying reciprocal translocations. Before treatment, 85% of pregnancies had resulted in spontaneous miscarriage and five couples had achieved a healthy live-birth delivery. Following treatment, 33% of pregnancies failed and 21of 59 couples had a healthy live-born child. The accuracy of diagnosis was 92% (8% false abnormal and 0% false normal results). The overall incidence of 2:2 alternate segregation products was 44% however, products consistent with 2:2 adjacent segregation were ∼twice as likely from male heterozygotes, and those with 3:1 disjunction were three times more likely from female heterozygotes. Our results indicate that up to three stimulation cycles per couple would give an ∼50% chance of a successful live birth, with the risk of miscarriage reduced to the level found in the general population. In our study, 87% of all normal/balanced embryos available were identified as being suitable for transfer. We conclude that PGD provides benefit for couples with high-risk translocations by reducing the risk of miscarriage and avoiding a pregnancy with an unbalanced form of the translocation; however, for fertile carriers of translocations with a low risk of conceiving a chromosomally unbalanced offspring, natural conception may be a more viable option.     

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver‐Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver‐Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well‐recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved. © 2002 Wiley‐Liss, Inc.     

PGD in female carriers of balanced Robertsonian and reciprocal translocations by first polar body analysis.

Preimplantation genetic diagnosis (PGD) using the first polar body (1PB) is a modality of PGD that can be used when the woman is the carrier of a genetic disease or of a balanced chromosomal reorganization. PGD using 1PB biopsy in carriers of balanced chromosome reorganizations has not become generalized. Here, we describe our experience based on the analysis of unfertilized or fresh, non-inseminated control oocytes, by fixing separately the 1PB and the corresponding oocyte, and on the study of six clinical cases of PGD using 1PB biopsy (four Robertsonian translocations and two reciprocal translocations). In fresh oocytes, the chromosome morphology of the 1PB was well preserved, and the results were always concordant for each oocyte-1PB pair. This indicates that the 1PB can be reliably used for the diagnosis of chromosome reorganizations. In these studies the technical problems encountered when performing PGD using 1PB biopsies for chromosome studies are also addressed. Three different strategies of 1PB biopsy (laser beam, partial zona dissection and acid Tyrode's) and two different protocols (intracytoplasmic sperm injection before or after 1PB biopsy) and their effect on the percentage of oocytes diagnosed and the fertilization rate, are discussed. In reciprocal translocation cases, published in the literature or studied by us, in which at least nine oocytes had been diagnosed, a correlation has been found between the frequency of nondisjunction observed and the theoretical recombination rate. To date, PGD by 1PB analysis alone or combined with blastomere biopsies in female carriers of chromosomal rearrangements has been used in 18 cases, with a further six cases reported here. A total of 325 cumulus-oocyte complexes have been obtained, of which 294 were biopsied and 224 were diagnosed. A total of 52 embryos was transferred, 19 of which implanted and 17 produced full-term pregnancies.     

染色体易位携带者的胚胎植入前遗传学诊断研究进展

染色体易位是常见的染色体结构异常。应用荧光原位杂交技术，染色体易位携带者可在胚胎植入前遗传学诊断的帮助下增加正常妊娠的机会。现就相互易位减数分裂的情况进行综述，并讨论应用荧光原位杂交技术对染色体易位携带者进行胚胎植入前遗传学诊断的策略。     

Partial trisomy 8q. Two case reports with maternal translocation and inverted insertion: phenotype analyses and reflections on the risk

Partial trisomy 8qter-->q23 or q24.1 has been reported in 15 literature cases. We add two further case reports here. Patient 1 inherited the derivative (2) of a balanced maternal reciprocal translocation t(2;8)(qter;q2300) after 2:2 disjunction and adjacent-1 segregation, and is trisomic for the segment 8qter-->q2300. Patient 2 inherited a recombinant (8) of a balanced maternal inverted insertion inv ins(8)(q1300;q2300q24.2) and is trisomic for the segment 8q24.2-->q2300. The phenotype of both patients is described and compared to the spectrum of symptoms established from the 15 literature cases. This spectrum contains all features observed with a frequency of > = 50%. Patient 1 had 35% of the features of this spectrum; Patient 2 had 47%. The intrauterine survival probability of unbalanced offspring is assumed to be the same in both cases, as nearly the same segments are trisomic. The pedigrees indicate that the inversion carrier may have a reduced production probability of unbalanced gametes and therefore a reduced risk compared to the translocation carrier.