Six families with balanced chromosome translocation associated with reproductive risks in Hainan Province: Case reports and review of the literature

Abstract

BACKGROUND

Balanced translocation refers to the process where breakage and reconnection of chromosomes occur at abnormal positions. As the genetic substance with balanced translocation in individuals does not change, which is usually characterized by normal phenotype and intelligence, the individuals seek medical service after many miscarriages, resulting in considerable mental and physical burdens of the family members. In the current era with rapid advances in detection technology, cytogenetic examination, as a definitive approach, still plays an essential role.

CASE SUMMARY

We report six cases with balanced chromosome translocation: Case 1: 46,XY,t(3;12)(q27;q24.1), infertility after 3 years of marriage; Case 2: 46,XX,t(4;16)(q31;q12), small uterus and irregular menstruation; Case 3: 46,XY,t(4;5)(q33;q13),9qh+, not pregnant after arrested fetal development; Case 4: 46,XX,t(11;17)(q13;p11.2), not pregnant after two times of spontaneous abortion; Case 5: 46,XX,t(10;13)(q24;q21.2), not pregnant after arrested fetal development for once; Case 6: 46,XX,t(1;4)(p36.1;q31.1), not pregnant after arrested fetal development for two times. The first four cases had chromosomal aberration karyotypes.

CONCLUSION

These results suggested that balanced chromosomal translocation carriers are associated with reproductive risks and a very high probability of abnormal pregnancy. The discovery of the first four reported chromosomal aberration karyotypes provides an important basis for studying the occurrence of genetic diseases.

Key Words: Reproductive risk, Balanced translocation, Abnormal pregnancy, Genetic counseling, Case report

Core tip: The genetic substance with balanced translocation in individuals does not change, which is usually characterized by normal phenotype. Here, we report six cases with balanced chromosome translocation: Case 1: 46,XY,t(3;12)(q27;q24.1), infertility for 3 years; Case 2: 46,XX,t(4;16)(q31;q12), small uterus and irregular menstruation; Case 3: 46,XY,t(4;5)(q33;q13),9qh+, infertility; Case 4: 46,XX,t(11;17)(q13;p11.2), two times of spontaneous abortion; Case 5: 46,XX,t(10;13)(q24;q21.2), arrested fetal development for one time; Case 6: 46,XX,t(1;4)(p36.1;q31.1), arrested fetal development for two times. This study suggested that balanced chromosomal translocation carriers are associated with reproductive risks. The first four reported chromosomal aberration karyotypes provide an important basis for studying the occurrence of genetic diseases.

INTRODUCTION

Chromosomal disorder is defined as a genetic disease caused by abnormalities in number, morphology, or structure of chromosomes, often resulting in miscarriage, congenital mental retardation, mental retardation, and multiple malformations clinically. This seriously threatens the health of humans. Chromosomal abnormalities cannot be treated in the current medical field, as they are irreversible. Balanced translocation is referred to as the situation where both breakage and reconnection of chromosomes occur at abnormal positions. Currently, the specific mechanisms underlying balanced translocation remain unclear. Translocation might be a completely harmless process or may cause serious health problems based on specific scenarios. In the first scenario, as the amount of individual chromosomal substance with balanced translocation does not change, which is usually characterized by normal phenotype and intelligence, the individuals look for medical services after undergoing many miscarriages. Chromosomes with balanced translocation can be inherited from parents or caused by the occurrence of new mutations[1]. Hence, in the present study, six families with balanced chromosome translocation are described, where four individuals had chromosomal aberration karyotypes, and so further observation and analyses were performed. Further verification of these detection results of abnormal karyotypes has significance in guiding patients with clinical indications, such as spontaneous abortion, infertility, mental retardation, and fetal ultrasound abnormalities[2].

CASE PRESENTATION

Chief complaints

(1) Case 1: Infertility after 3 years of marriage; (2) Case 2: Irregular menstruation; (3) Case 3: Not pregnant after arrested fetal development; (4) Case 4: Not pregnant after two times of spontaneous abortion; (5) Case 5: Not pregnant after arrested fetal development for one time; and (6) Case 6: Not pregnant after arrested fetal development for two times.

History of present illness

Five patients (Cases 1, 3, 4, 5, and 6) had infertility, and Case 2 had small uterus and irregular menstruation.

History of past illness

(1) Case 1: No significant past medical history; (2) Case 2: She received long-term traditional Chinese medicine for menstrual induction. The specific drugs and time were unknown. The uterus was small in size, and menstruation showed brown secretions; (3) Case 3: The medical abortion was reported during the first gestation, and arrested fetal development was reported after 60 d of pregnancy during the second gestation; (4) Case 4: Spontaneous abortion was reported after 50 d of pregnancy for two gestations; (5) Case 5: After 3 years of marriage, she underwent miscarriage after 1 mo of pregnancy due to no fetal heart. During her second pregnancy, blood was seen after 3 mo, and developmental arrest was noted. When engaged in physical work, she reported physical weakness, and advanced menstruation occurred often; and (6) Case 6: Arrested fetal development was observed after 60 d of pregnancy during the two gestations.

Personal and family history

Five patients (Cases 1, 3, 4, 5, and 6) had no significant personal or family history, and Case 2 had small uterus and irregular menstruation, but had no significant personal or family history.

Physical examination upon admission

(1) Case 1: The proband was a 30-year-old man who was 170 cm in height, and his phenotypic features and intelligence appeared normal; (2) Case 2: The proband was a 22-year-old unmarried woman who was 158 cm in height, and her phenotype and intelligence were normal; (3) Case 3: The proband was a 28-year-old man who was 172 cm in height, and his phenotype and intelligence were normal; (4) Case 4: The proband was a 32-year-old woman with a height of 153 cm, and her phenotype and intelligence were normal; (5) Case 5: The proband was a 24-year-old woman with a height of 158 cm, and her phenotype and intelligence were normal; and (6) Case 6: The proband was a 32-year-old woman with a height of 160 cm, and her phenotype and intelligence were normal.

Laboratory examinations

(1) Case 1: The results of semen examination based on three items (UU-DNA, CT-DNA, and NG-DNA) were normal, and showed anti-sperm antibody (-); (2) Case 2: Five items for sex hormones were unremarkable [luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), progesterone (PRG), and prolactin (PRL)], and the total testosterone (TES) level was normal; (3) Case 3: The results of routine semen tests were unremarkable; (4) Case 4: Five items of sex hormones (LH, FSH, E2, PRG, and PRL) were unremarkable. TES and insulin levels were normal. She had anti-sperm antibody (-); (5) Case 5: The five sex hormones (such as LH, FSH, E2, PRG, and PRL) were unremarkable. Her TES level was normal; and (6) Case 6: The five items of sex hormones (LH, FSH, E2, PRG, and PRL) were unremarkable. The TES was normal. Anti-sperm antibody was negative, and –α 4.2 thalassemia gene deletion type (heterozygous) was observed.

Imaging examinations

Five patients (Cases 1, 3, 4, 5, and 6) had normal imaging examinations, and Scanning under bladder filling in Case 2 showed that the uterus was small in size (3.9 mm × 2.5 mm × 3.1 mm).

FINAL DIAGNOSIS

Four chromosomal aberration karyotypes were identified by the expert group of Chinese Database of Human Abnormal Chromosome Karyotypes. No relevant report was found in the “Chinese Human Chromosome Abnormality Karyotype Database”, “Cytogenetics Database”. Therefore, the karyotypes were included in the “Chinese Human Chromosome Abnormal Nuclei Database” (Database Numbers: 4222, 4059, 4238, and 4223). The genetic pedigree diagrams were drawn using Microsoft PowerPoint (Figures 1-6). The comparison of family history is shown in Table 1.

Table 1 History comparison table of the six families.

Items	Family 1	Family 2	Family 3	Family 4	Family 5	Family 6
Area	Haikou, Hainan Province	Danzhou, Hainan Province	Wenchang, Hainan Province	Dongfang, Hainan Province	Haikou, Hainan Province	Qionghai, Hainan Province
Age (yr)	30	22	28	32	24	32
Sex	M	F	M	F	F	F
Ethnicity	Han	Han	Han	Han	Han	Han
Occupation	Office worker	Office worker	Civil servant	Office worker	Civil servant	Civil servant
Height (cm)	170	158	172	153	158	160
Visiting time	2016	2015	2014	2014	2016	2016
Reasons for medical visit	Infertility after 3 yr of marriage	Small uterus, irregular menstruation	Not pregnant after arrested fetal development	Not pregnant after two times of spontaneous abortion	Not pregnant after arrested fetal development for one time	Not pregnant after arrested fetal development for two times
Pregnancy history of self or spouse	G0P0	Unmarried	G2P0	G2P0	G1P0	G3P0
Proband karyotype	46,XY,t(3;12)(q27;q24.1)(Database number: 4222)	46,XX,t(4;16)(q31;q12)	46,XY,t(4;5)(q33;q13),9qh+	46,XX,t(11;17)(q13;p11.2)(Database number: 4059)	46,XX,t(10;13)(q24;q21.2)(Database number: 4238)	46,XX,t(1;4)(p36.1;q31.1)(Database number: 4223)
Spouse karyotype	46,XX	0	46,XX	46,XY	46,XY	46,XY
Spouse’s age	30	0	25	38	28	35

Figure 1 G-banding chromosome analysis and genetic pedigree diagram of Case 1. A: Karyogram (Database Number: 4222): 46,XY,t(3;12)(q27;q24.1); B: Genetic pedigree diagram.

Figure 2 G-banding chromosome analysis and genetic pedigree diagram of Case 2. A: Karyogram: 46,XX,t(4;16)(q31;q12); B: Genetic pedigree diagram.

Figure 3 G-banding chromosome analysis and genetic pedigree diagram of Case 3. A: Karyogram: 46,XY,t(4;5)(q33;q13),9qh+; B: Genetic pedigree diagram.

Figure 4 G-banding chromosome analysis and genetic pedigree diagram of Case 4. A: Karyogram (Database Number: 4059): 46,XX,t(11;17)(q13;p11.2); B: Genetic pedigree diagram.

Figure 5 G-banding chromosome analysis and genetic pedigree diagram of Case 5. A: Karyogram (Database Number: 4238): 46,XX,t(10;13)(q24;q21.2); B: Genetic pedigree diagram.

Figure 6 G-banding chromosome analysis and genetic pedigree diagram of Case 6. A: Karyogram (Database Number: 4223): 46,XX,t(1;4)(p36.1;q31.1); B: Genetic pedigree diagram.

Case 1

G-banding chromosome analysis of peripheral blood (Database Number: 4222) showed 46,XY,t(3;12)(q27;q24.1) (Figure 1A). The genetic pedigree diagram is shown in Figure 1B.

Case 2

G-banding chromosome analysis of peripheral blood showed 46,XX,t(4;16)(q31;q12) (Figure 2A). The genetic pedigree diagram is shown in Figure 2B.

Case 3

G-banding chromosome analysis of peripheral blood showed 46,XY,t(4;5) (q33;q13),9qh+ (Figure 3A). The genetic pedigree diagram is shown in Figure 3B.

Case 4

G-banding chromosome analysis of peripheral blood (Database Number: 4059) showed 46,XX,t(11;17)(q13;p11.2) (Figure 4A). The genetic pedigree diagram was shown in Figure 4B.

Case 5

G-banding chromosome analysis of peripheral blood (Database Number: 4238) showed 46,XX,t(10;13)(q24;q21.2) (Figure 5A). The genetic pedigree diagram was shown in Figure 5B.

Case 6

G-banding chromosome analysis of peripheral blood (Database Number: 4223) showed 46,XX,t(1;4)(p36.1;q31.1) (Figure 6A). The genetic pedigree diagram was shown in Figure 6B.

TREATMENT

Case 1

In 2016, he underwent in vitro fertilization-embryo transfer (IVF-ET).

Case 2

The patient took drugs such as estrogen and progesterone to adjust the menstrual cycle.

Cases 3 and 4

In 2014, they underwent IVF-ET.

Cases 5 and 6

In 2016, they underwent IVF-ET.

OUTCOME AND FOLLOW-UP

(1) Case 1: No successful pregnancy; (2) Case 2: Menstruation was basically normal; (3) Case 3: No successful pregnancy; (4) Case 4: No successful pregnancy; (5) Case 5: No successful pregnancy; and (6) Case 6: Had first successful gestation for 5 mo in January 2019.

DISCUSSION

The six probands in the present study had a history of abnormal pregnancy or irregular menstruation. Cytogenetic karyotype analysis showed autosomal balanced translocation, and four of them were identified to have the world’s first reported chromosomal aberration karyotypes. Despite the rapid development of molecular technology, cytogenetic analysis remains an indispensable tool[3,4].

Chromosome breakage and recombination occur during spermatogenesis or oogenesis, or during fertilization process. The problem caused by these changes has a small probability, and moreover, these changes are unknown. The case reports by Sha et al[5] and Mas et al[6] showed that complex balanced translocation may be an important cause of oligospermia, suggesting that chromosomes with balanced translocation impedes the meiosis of germ cells, and leads to the damage of spermatogenesis. The reciprocal translocation of chromosomes occurs in the process of meiosis during gametogenesis. When the chromosomes are homologously paired, a quadriradial chromosome is formed. By alternate, adjacent, and 3:1 separations, 18 gametes are formed, in which there is a normal one and a balanced one, and the remaining 16 gametes are unbalanced. From references[7-9], we know that the development of zygotes formed by these unbalanced gametes through fertilization forms a monosome or partial monosome, trisome, or partial trisome, leading to adverse outcomes of spontaneous abortion, stillbirth, fetal malformations, or neonatal death. Therefore, the likelihood of abnormal pregnancy for carriers is quite high, and this also explains the reasons for the six families with a history of abnormal pregnancy or irregular menstruation.

The chromosomal abnormality rate in the general population in China is 0.5%-1.0%, and the rate of chromosomal abnormalities in patients with a history of adverse pregnancy is 2%-10%[10,11]. We retrospectively analyzed 36 articles from a population with a poor maternal history (Table 2): Among them, the detection rate of chromosomal abnormalities in 20 provinces and cities in China was 5.86% (2703/46133), the incidence of autosomal equilibrium translocation was 1.74% (804/46133), the detection rate of chromosomal abnormalities in 16 countries was 5.15% (1139/22134), and the incidence of autosomal equilibrium translocation was 2.35% (521/22134). The total detection rate of chromosomal abnormalities in patients with a poor maternal history in 20 provinces and cities in China and 16 countries was 5.62% (3842/68267), basically consistent with the aforementioned literature. The total incidence of autosomal balanced translocation was 1.97% (1325/68267). This analysis demonstrates that chromosomal abnormalities may be one of the important causes of a poor maternal history and it is necessary to carry out cytogenetic examination.

Table 2 Chromosome detection rates in China’s 20 provinces and cities and 16 countries.

No	Region	Anomaly chromosome detection rate	Incidence of autosomal balanced translocation	Medical history
1	Hainan Province, China[21]	10.5% (353/3353)	0.44% (15/3353)	Genetic counselors
2	Gansu Province, China[22]	3.91% (51/1304)	1% (13/1304)	Genetic counselors
3	Ningxia Hui Autonomous Region, China[23]	3.52% (36/1024)	2.5% (26/1024)	Recurrent spontaneous abortion
4	Shanxi Province, China[24]	23.76% (307/1292)	14% (185/1292)	Abnormal child-bearing history
5	Shandong Province, China[25]	4.73% (309/6534)	0.39% (26/6534)	Abnormal child-bearing history
6	Hebei Province, China[26]	2.09% (70/3348)	1.1% (36/3348)	Infertility
7	Zhejiang Province, China[27]	6.6% (106/1601)	0.5% (8/1601)	Infertility
8	Shanghai, China[28]	3.96% (111/2798)	1.24% (37/2798)	Natural abortion
9	Fujian Province, China[29]	4.32% (87/2110)	1.18% (25/2110)	Abnormal child-bearing history
10	Beijing, China[30]	7 % (28/400)	2.5% (10/400)	Abnormal child-bearing history
11	Anhui Province, China[31]	5.35% (353/6600)	2.98% (197/6600)	Infertility
12	Hubei Province, China[32]	20.2% (315/1559)	3.72% (58/1559)	Recurrent abortion
13	Guizhou Province, China[33]	5.12% (32/625)	4.16% (26/625)	Abnormal child-bearing history
14	Yunnan Province, China[34]	1.5% (3/200)	1% (2/200)	Abnormal child-bearing history
15	Guangdong Province, China[35]	10.37% (132/1273)	1.1% (14/1273)	Abnormal child-bearing history
16	Jiangsu Province, China[36]	1.7% (90/5292)	0.6% (32/5292)	Infertility
17	Hunan Province, China[37]	3.14% (111/3540)	1.67% (59/3540)	Natural abortion
18	Heilongjiang Province, China[38]	4.51% (82/455)	3.3% (15/455)	Genetic counselors
19	Henan Province, China[39]	11.5% (21/182)	4.4% (8/182)	Natural abortion
20	Sichuan Province, China[40]	4% (106/2643)	0.45% (12/2643)	Genetic counselors
21	Republic of Macedonia[41]	0.47% (16/3800)	0.21% (8/3800)	Natural abortion
22	United Kingdom of Great Britain and Northern Ireland[42]	3.52% (56/1590)	2.26% (36/1590)	Recurrent abortion
23	Turkey[43]	4.1% (124/3020)	0.99% (30/3020)	Natural abortion
24	Republic of India[44]	6.8% (54/788)	5.9% (47/788)	Recurrent abortion
25	Japan[45]	4.3% (55/1278)	1.5% (19/1278)	Recurrent abortion
26	Morocco[46]	11% (137/1254)	2.71% (34/1254)	Recurrent abortion
27	Islamic Republic of Iran[47]	11.7% (170/1456)	7.35% (107/1456)	Recurrent abortion
28	the United Mexican States[48]	7.6% (24/316)	1.27% (4/316)	Recurrent abortion
29	Sultanate of Oman[49]	3.42% (26/760)	2.8% (21/760)	Recurrent abortion
30	Kingdom of Saudi Arabia[50]	7.2% (154/2148)	3.35% (72/2148)	Recurrent abortion
31	Magyarország[51]	3.39% (8/236)	0.85% (2/236)	Recurrent abortion
32	Islamic Republic of Pakistan[52]	5.3% (32/600)	2.3% (14/600)	Recurrent abortion
33	The Republic Of Poland[53]	6.2% (16/258)	4.65% (12/258)	Recurrent abortion
34	Russia[54]	2.37% (81/3414)	1.9% (65/3414)	Infertility
35	Tunis[55]	8.5% (28/326)	3.68% (12/326)	Recurrent abortion
36	Spain[56]	17.7% (158/890)	4.27% (38/890)	Recurrent abortion
Total (1-20)		5.86% (2703/46133)	1.74% (804/46133)
Total (21-36)		5.15% (1139/22134)	2.35% (521/22134)
Total (1-36)		5.62% (3842/68267)	1.97% (1325/68267)

The study conducted by Clementini et al[12] reported that each couple should undergo karyotyping in the infertility centers in Europe before receiving assisted reproductive therapy, with an aim to reduce the incidence of miscarriage or congenital anomalies. Studies have concluded that all women who require assisted reproductive therapy should undergo cytogenetic screening.

Recurrent miscarriage (RM) is defined as two or more consecutive spontaneous abortions, which accounted for 1% to 3% in couples[13,14]. Zhu et al[15] studied 42 balanced translocation carriers with a total of 90 pregnancies, in which spontaneous abortion occurred for 75 times during the early pregnancy, reaching an incidence of up to 83.4%. From the pedigree chart of Case 5 in this study, the mother of the proband was also accompanied by four adverse pregnancies. Although chromosomal detection was not performed, it was speculated to be inherited from the mother. The probands in the five families showed a history of adverse pregnancies. Multiple miscarriages can lead to emotional and physical trauma. To avoid the birth of infants with chromosomal abnormalities, intrauterine diagnosis is recommended for balanced chromosome translocation carriers at 16 to 20 wk of pregnancy. For couples with balanced translocations, the probability of birth of normal offspring is very small, and so assisted reproductive technology is recommended and preimplantation genetic diagnosis should be performed. Moreover, transplantation of normal embryos can significantly reduce the reproductive risk and pain of balanced translocation carriers, thus achieving the purpose of good childbearing and sound child-bearing[16], for example, Case 6 reported successful conception after about 3 years.

Chromosomal examinations should be performed on those with a history of abnormal pregnancy, and if possible, the chromosomes of family members should be examined. A computerized database generated from the literature on cytogenetic studies in couples experiencing repeated pregnancy losses has been put in place at the University of Quebec at Chicoutimi. It contains data on 22199 couples (44398 individuals). It also appears that only translations are linked to a higher risk of pregnancy wastage[17]. Bernardi et al[18] suggested chromosome testing of the second miscarriage, to determine whether a recurrent pregnancy loss (RPL) evaluation is required. Selective RPL evaluation, which is based upon chromosome testing of the subsequent miscarriage, is a cost-saving strategy for couples with RPL when compared with universal RPL evaluation.

Kaneko et al[19] believed that although the detection causes a variety of complex psychological problems for the probands, they believed that it was important to be aware as to which parent to inherit from. For example, studies by Bache et al[20] resulted in changes in genetic counseling practice in Denmark. When balanced chromosome translocation carriers aged over 18 years underwent examinations during prenatal period or childhood, parents will receive a letter to remind the family regarding the importance of potential reproductive risks involved and recommend participation in genetic counseling. This helps us to identify the risks faced by future generations, and is extremely necessary for individuals to undergo targeted examinations as well as provide guidance for good childbearing and sound child-bearing.

The detection of new karyotypes of human chromosomes provides abundant data of medical genetics for genetic counseling and prenatal diagnosis. Our four cases had first reported chromosomal aberration karyotypes in this study, which can help us to better understand the balanced autosomal translocation involved in infertility. Also, the discovery and declaration of abnormal karyotypes provide an important basis for studying the occurrence, development, prevention, clinical diagnosis, and treatment of genetic diseases. Furthermore, pre-pregnancy and prenatal diagnosis is also important for good childbearing and sound child-bearing, decreasing the birth of infants with malformations and hypophrenia.

However, our study had a few limitations, such as inclusion of small sample size and unavailability of cytogenetic analysis of miscarriage materials, history of the diagnosis, and previous history of treatment. In future, a study with large sample size should be conducted to provide more useful insight for clinical diagnosis.

CONCLUSION

This study suggested that balanced chromosomal translocation carriers are associated with reproductive risks. The first four reported chromosomal aberration karyotypes provide an important basis for studying the occurrence of genetic diseases. This analysis demonstrates that chromosomal abnormalities may be one of the important causes of a poor maternal history and it is necessary to carry out cytogenetic examination.