Reproductive Outcomes in 101 Couples with Balanced Chromosomal Rearrangements
Received Date: Apr 13, 2018 / Accepted Date: May 03, 2018 / Published Date: May 07, 2018
Background: There are very few studies on reproductive outcomes in couples with balanced chromosomal translocations. Findings of such studies can shed light on the possible future outcomes and help in genetic counselling. Objectives: The overall objectives of this study were to report the various chromosomal balanced rearrangements in couples with history of bad reproductive history, to analyse the reproductive outcomes prior to the evaluation and to compare the chromosomal findings with the similar available data from literature. Methods: Reproductive history of couples identified with balanced chromosomal translocations at Genetic Health and Research Centre, Nashik was studied retrospectively, and the various pregnancy outcomes were tabulated and compared with the available literature data. Results: Out of 1580 couples investigated for chromosomal abnormalities for the various indications like recurrent miscarriages, infertility, intrauterine deaths, stillbirths, children with birth defects and neonatal deaths, 101 (6.39%) were found to be carriers of balanced chromosomal rearrangements. A total of 334 pregnancies (average 3.2) were documented in all these carriers. The mean maternal age at the time of evaluation was 29.4 years. Various reproductive outcomes documented were pregnancy losses in 290 couples (2.87 per couple), abnormal births in 25 couples, infertility in 9 couples and normal birth in 19 couples. Conclusion: Karyotyping of couples with bad reproductive outcomes is highly useful for further genetic counselling, appropriate management and close monitoring in subsequent pregnancies. Carriers of balanced chromosomal translocations have better chances of having a normal live birth, however the risk of having the birth of offspring with chromosomal abnormality need to be taken into consideration and prenatal diagnosis offered in all future viable pregnancies.
Keywords: Reproductive outcome; Recurrent miscarriage; Infertility; Balanced chromosomal translocations; Karyotype
Number of factors are known to be responsible for the compromised reproductive potential in couples. Balanced chromosomal rearrangements are reported in 0.6% of couples with infertility, 9.2% of couples with recurrent miscarriages and 0.2% in the neonates . Individuals with the balanced chromosomal rearrangements are usually phenotypically normal and are unaware of the reproductive risks. They have higher chances of having chromosomally unbalanced embryos, which can lead to infertility or spontaneous miscarriages or children with congenital anomalies . Moreover, offspring of the carrier parents with apparently balanced translocations may produce a clinical phenotype due to gene involvement in the breakpoint region . Balanced translocations are reported to significantly higher in females than males and this disparity is said to be due to the fact only one egg is released in the female every month compared to millions in a man every day . Incidence of chromosomally abnormal gametes is variable in the different carriers of translocations involving the same chromosomes, resulting in higher live birth rates in male carriers of balanced chromosomal translocations  (Figure 1).
Live births are documented in nearly two thirds of pregnancies in carriers of balanced translocations subsequent to the evaluation [3,6]. Live birth rates are also variable depending on the nature of the chromosomal rearrangements in the carrier parents. Carriers of chromosome inversion (mostly involving chromosome 9) have a significantly higher live birth rate than the carriers of the reciprocal translocations [6,7] has reported a higher risk of recurrent miscarriages or progeny with congenital malformations in the carriers of complex chromosomal rearrangements. The aim of this study was to report the incidence and types of various chromosomal rearrangements and their association with the reproductive outcomes in the carrier couples (Table 1).
|Indication for investigation||Balanced translocation noted in parent|
|Pregnancy Loss (including spontaneous miscarriages, IUDs,
Still births and Medical terminations of pregnancies due to major
malformations identified with USG) (n= Females 30 and Male 20)
|46, XX, t (7q:12q)||46, XY, t (3q:6p)|
|46, XX, t (9q:16p)||46, XY, t (1q:5p)|
|46, XX, der (13) t (21;13) (q12-ter; qter)||46, XY, t (19q; Yq)|
|46, XX, der (1), t (1q;10q)||46, XY, t (Y;9) (q11-ter; q11)|
|46, XX, t (6q;12p)||46, XY, t (10;14) (q26; q11)|
|46, XX, t (10q;14q)||46, XY, t (2;15) (p11; p12)|
|46, XX, t (12q:14q)||46, XY, t (4;7) (p15.2-pter; q36)|
|46, XX, t (5q;2p)||46, XY, t (14q;16q)|
|46, XX, t (6q;11p)||46, XY, t (11p;22q)|
|46, XX, t (2q;13p)||46, XY, t (10;14) (qter; q11)|
|46, XX, t (13q;6q)||46, XY, t (Y;14) (q12;p11)|
|46, XX, t (3;6) (qter:q12-qter)||46, XY, t (4p;14q)|
|46, XX, t (X;4) (pter;p21-pter))||46, XY, t (7;17) (q32;q21)|
|46, XX, t (6;18) (q63-qter;qter)||46, XY, t (3p;21q)|
|46, XX, t (3;5) (q21;q13)||46, XY, t (6q;18q)|
|46, XX, t (10;21) (p11;q11)||46, XY, t (4;7) (p15;q36)|
|46, XX, t (8q;22q)||46, XY, der (21) t (3;22) (p11;p11)|
|46, XX, t (13;9) (q32;q24)||46, XY, t (12q:14q)|
|46, XX, t (12;5) (q22;pter)||46, XY, der (6), t (5;10) (q24;qter)|
|46, XX, der (6), t (4q;6q)||46, XY, der (16), t (16;18) (qter;q21-qter)|
|46, XX, t (7;7) (p21-ter:qter)||--|
|46, XX, t (1;4) (p35;qter)||--|
|46, XX, t (11;22) (qter;q13)||--|
|46, XX, t (4;7) (q31;p13)||--|
|46, XX, t (5p;6q)||--|
|46, XX, t (14p:18q)||--|
|46, XX, t (2q;18p)||--|
|46, XX, t (7;11) (q22;q14)||--|
|46, XX, t (9q;13q)||--|
|46, XX, t (7q;21p)||--|
|Child with congenital malformations (n= Females 11 and Males 3)||46, XX, der (6), t (10:7) (q22;qter:qter)||46, XY, der (16), t (16:18) (qter:q21-qter)|
|46, XX, t (4:15), (qter:q1.3-qter)||46, XY, der (6), t (6:10) (q24:qter)|
|46, XX, der (9), t (9:13) (qter: q22)||46, XY, t (12:14)|
|46, XX, der (13), t (2:13) (q31-qter:p23)||--|
|46, XX, der (18), t (2:18) (q33-ter:p11)||--|
|46, XX, t (14:7) (q12:q3.6)||--|
|46, XX, der (13), t (2:13) (q23-ter: q31)||--|
|46, XX, t (11:3) (q22:qter)||--|
|46, XX, t (6:9) (p2.12-ter:qter)||--|
|46, XX, der (1) t (X:1), 9q22-ter:qter)||--|
|46, XX, t (6:18), (q63-ter:qter)||--|
|Infertility (n= Females 4 and Male 2)||46, XX, t (9:13) (q22-ter: qter)||46, XY, t (6:11) (q24-ter: qter)|
|46, XX, t (10:21) (p11-ter:p11||46, XY, der (5), t (5:6) (q25-ter:qter)|
|46, XX, t (6:10) (q22:qter)||--|
|46, XX, t (9:12) (p1.1-ter:qter)||--|
Table 1: Indications for chromosomal analysis and carriers of balanced translocations.
Material and Methods
It is a Retrospective study of 1580 coupes reported at Genetic Health and Research Centre, Nashik, Maharashtra between 2004-2015. Couples referred for chromosomal analysis for various indications like infertility, recurrent miscarriages, intrauterine deaths, stillbirths, birth of babies with congenital anomalies or neonatal deaths were included in this study. Couples with balanced chromosomal rearrangements were included in the analysis and those with numerical abnormalities were excluded. Reproductive history prior to the evaluation was noted in detail and analysed.
Chromosome analysis from peripheral blood was performed as per the standard procedure. Giemsa-Trypsin banding procedure was used to study the chromosomes at 500 band resolutions. A minimum of 20 metaphases were studied and 2 were analysed in detail for the structural variations. Karyotypes were reported according to the ISCN standards . Consent of all the cases were obtained for study.
Total number of couples evaluated for the abnormal reproductive outcomes during 2004 to 2017 were 1580, out of which balanced chromosomal rearrangements were observed in one of the partners in 101 (6.39%) couples. Out of these 101 carriers, females were 63 and males were 38. The prior reproductive history revealed, 8 couples with infertility a total of 334 documented pregnancies (the mean number of pregnancies per couple was 3.3- SD 2.6 Pregnancies). Out of 334 clinical pregnancies, 290 pregnancies were lost (including spontaneous miscarriages, IUDs, still births and Medical terminations of pregnancies due to major malformations identified with USG) with an average of 2.87 (290/101) pregnancies lost per couple, 44 (13.2%) live births including 25 babies with birth defects and 19 normal babies. Since the reproductive outcomes studied in these couples were prior to evaluation, prenatal diagnosis was not offered in any of the pregnancies and all these pregnancies were natural. The average duration of marriage was 4.2 years (in the range of 2 to 11 years).
Chromosomes involved in the reciprocal translocations
Out of total 70 carriers of the reciprocal translocations studied 45 were the females and 25 were the males. The most commonly involved chromosome in the female carriers was 6 (10 carriers), followed by chromosome 13 (9 carriers), 7 (8 carriers), 9 (7 carriers), 2 and 10 (6 carriers each), 18 (5 carriers), 5, 11, 12 and 21 (four carriers each). Chromosomes which were not seen involved in the translocations were 17, 19 and 20.
Most frequently involved chromosome in the male carriers was chromosome 15 (5 carriers), followed by 6 and 10 (four carriers each), 3, 5, 7, 16, 18 and Y (three carriers each), 4, 11, 12 and 22 (two carriers each). Chromosomes not observed in the translocations were 8, 13 and 20.
Total number of documented pregnancies in all these carriers of reciprocal translocation were 270, out of which 248 leads to pregnancy losses and 25 the live births. Pregnancy losses included 239 spontaneous miscarriages before 20 weeks, 7 intrauterine deaths, 4 still births and 16 elective terminations based on the USG findings suggestive of multiple malformations. Out of the 25 documented live births, 11 were normal and 14 were babies born with congenital malformations.
Chromosomes involved in the Robertsonian translocations
Total carriers of Robertsonian translocation identified were 31, out of which 18 were the females and 13 were the males. Chromosomes most frequently involved in female carriers, in descending order were 13 and 21 (11 carriers each), 14 (10 carriers), 22 (three carriers), 15 (one carrier). The most common translocations observed in females were 13/14 and 14/21 (five times each), followed by 13/21, 13/13 (two times each), 15/21, 21/22, 21/21, 22/22 (one time each).
The most frequently involved chromosome in the male carriers of Robertsonian translocation was chromosome 14 (11 times), followed by 21 (six times), 13 (5 times), 15 (3 times) and 22(one time). The most commonly seen Robertsonian translocations in males were 13/14 (five times), 14/21 (three times), 14/15 (two times), 15/21, 21/21 and 14/21 (one time each) (Table 2).
|Indication for investigation||Balanced Translocation noted in parent|
|pregnancy loss (spontaneous miscarriages, IUDs,
still births and MTPs due to major malformations
identified with USG) (n= Females 9 and Males 8))
|45, XX, t (13q:14q)||45, XY, t (13q:14q)|
|45, XX, t (13q:14q)||45, XY, t (13q:14q)|
|45, XX, t (13q:14q)||45, XY, t (13q:14q)|
|45, XX, t (13q:14q)||45, XY, t (13q:14q)|
|45, XX, t (14q;21q)||46, XY, t (14q;21q)|
|45, XX, t (14q;21q)||46, XY, t (14q;21q)|
|45, XX, t (21q;22q)||45, XY, t (14q;15q)|
|45, XX, t (22q:22q)||45, XY, t (14q;15q)|
|45, XX, t (13q;21q)|
|Child with congenital malformations (n= Female 7and Males 4)||45, XX, t (13q:21q)||45, XY, t (15q:21q)|
|45, XX, t (14q:21q)||45, XY, t (14q:22q)|
|45, XX, t (14q:21q)||45, XY, t (21q:21q)|
|45, XX, t (14q:21q)||45, XY, t (14q:21q)|
|45, XX, t (13q:14q)||--|
|45,XX, t (13q;13q)||--|
|45, XX, t (15q:21q)||--|
|Infertility (n= Females 2 and Males 1)||45, XX, t (21:21) (q11:q11)||45, XY, t (13q:14q)|
|45,XX, t (13q;13q)|
Table 2: Indications for chromosomal analysis and carriers of Robertsonian translocations.
Number of pregnancies documented in these carriers of Robertsonian translocations were 64, leading to various reproductive outcomes as 45 pregnancy losses, including 34 spontaneous abortions before 20 weeks of gestation, 4 IUDs, 2 still births and 5 elective terminations. Number of live births documented were 19 including 8 normal babies born and 11 babies with multiple congenital malformations.
The overall live birth rate was seen higher in the carriers of Robertsonian translocations (29.7%) than the reciprocal translocation carriers (9.25%). Similarly, the abnormal live birth rate was observed to be much higher in the Carriers of Robertsonian translocations (17.2%) than the reciprocal translocations (5.2%).
Stephenson et al. and Suguiura- Ogasawara et al. have reported structural chromosomal rearrangements in 2.7% (51/1893) and 7.8% (100/1284) of the couples with recurrent miscarriages, respectively [6,9]. They have included the chromosomal rearrangements other than the balanced translocations in their analysis. Present study however, has included only the carriers of balanced chromosomal translocations with a frequency of 6.4% (101/1580).
Balanced chromosomal translocation carriers generally do not have any loss or gain of the genetic information and are clinically normal. Such translocations can be inherited from generations to generations without being detected . An apparent balanced chromosomal translocation can lead to gene disruption or altered gene expression and thus may cause a clinical phenotype [3,11]. In the current study, out of 101 carriers, none had a clinically significant phenotype.
There are number of studies reporting higher risk of miscarriage, still births or birth of offspring with unbalanced karyotypes and mental retardation in the carriers of balanced chromosomal rearrangements [4,9,12,13]. Findings of the current study are consistent with these earlier studies. Current study shows that 86.8% of all the documented pregnancies with an average of 2.3 pregnancies were lost (including spontaneous miscarriages, intrauterine deaths, still births and the elective terminations due to abnormal USG) per couple, over an average duration of 4.2 years of marriage. The number of pregnancies lost were found to be significantly higher in carriers with reciprocal translocations (91.9%) than in carriers with the Robertsonian translocations (65.5%) with an average pregnancy of 3.54 and 1.35, respectively per couple.
In couples with recurrent miscarriages, the frequency of balanced chromosomal translocations has been reported to be more in females than males and it is stated to be due to the fact that the chromosomal rearrangements in females are compatible with fertility, whereas these are not-compatible with fertility in males (A. Lippman-Hand and [4,14]. The balanced chromosomal rearrangements in females (62.4%) in the current study were observed to be nearly twice than in males (37.6%).
Stephenson have studied the reproductive outcomes in carriers of balanced chromosomal translocations with history of recurrent miscarriages prior to and subsequent to the evaluation . They found a significant difference in the live birth rates and concluded that careful investigations of concomitant factors and follow up close monitoring in further pregnancies results in successful outcomes in nearly two third cases. In the current study, reproductive outcomes in the carrier couples has been studied only prior to evaluation and the live birth rate was found to be 13.2% (44/334), which in the study of Stephenson prior to evaluation has been reported to be 18.6% (51/188). Current study live birth rates included 25 (7.5%) offspring with congenital malformations and 19 (5.5%) normal offspring’s, whereas there were no live births with congenital malformations reported in the study of . Madan K has reported reproductive outcomes in carriers of complex chromosomal rearrangements, similar to the current study.
Carriers of balanced Robertsonian translocations have a higher live birth rate as compared to the carriers of balanced reciprocal translocations. Zhang has studied 503 pregnancies in the carriers of balanced chromosomal translocations prior and subsequent to the evaluation and reported spontaneous miscarriages in 81.7%, elective terminations because of fatal abnormalities in 3.2%, birth defects in 7.2%, normal offspring’s in 8% of pregnancies. Current study has studied the reproductive outcomes prior to evaluation and has reported spontaneous miscarriages in 75.4% (252/334) pregnancies, elective terminations due to fatal abnormalities in 6.3% (21/334), intrauterine deaths and still births in 5.1% (17/334) birth defects in 7.5% (25/334), normal live-births in 5.7% (19/334) pregnancies.
Zhang has reported normal live births and births with defects in higher frequencies in the carriers of non-homologous Robertsonian translocations (16.7% and 22.9%) respectively) as compared to carriers of reciprocal translocations (6.6% and 5.7% respectively) . There were 2 babies born with birth defects (8%) and no normal births out of 25 pregnancies in the carriers of homologous Robertsonian translocations. Current study findings are consistent with their findings and shows the higher frequencies of normal births and births with defects in the carriers of non-homologous Robertsonian translocations (12.5% and 17.2% respectively) as compared to the carriers of reciprocal translocations (4.1% and 5.2% respectively). Out of 16 pregnancies in the 5 carriers of homologous Robertsonian translocations (13/13- 2, 21/21-2 and 22/22-1) in the current study, there were 3 births (18.8%) with defects and no normal live births.
The most commonly observed chromosome in the reciprocal translocation was chromosome 6 (14/140) and the most commonly observed Robertsonian translocation was 13/14 (10/31) in the current study, which is consistent with the findings of MD Stephenson.
Carriers of balanced chromosomal translocations are usually missed, and they are at very high risk of bad obstetric outcomes including fatal losses and birth of the abnormal babies. Therefore, chromosomal analysis of the couples with reproductive losses and abnormal offspring’s is highly recommended for further genetic counselling and prevention of birth of chromosomally abnormal babies. The chances of having a normal child birth in subsequent pregnancies depend on the types of chromosomes involved in the translocations and thus genetic counselling prior to the further pregnancy management is highly useful. Post-evaluation follows up study of all these cases with balanced chromosomal translocations would be certainly beneficial for getting the more accurate reproductive outcomes.
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Citation: Chopade D, Gangane S, Chopade S, Harde H (2018) Reproductive Outcomes in 101 Couples with Balanced Chromosomal Rearrangements. Human Genet Embryol 8: 150. DOI: 10.4172/2161-0436.1000150
Copyright: © 2018 Chopade D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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