Abstract
Recurrent pregnancy loss is a phenomenon caused by many etiologies. The majority of these causes are chromosomal anomalies. In this case report, cytogenetic analysis was performed on the family who consulted our department with the complaint of recurrent pregnancy loss. A normal karyotype was found in the female (46, XX); however, t(2;7)(p23;q35) translocation was detected in the male. Reciprocal translocations are a common class of chromosomal abnormalities, and we anticipate this case of translocation will be a new cause for recurrent pregnancy loss. In the analysis, preparations at the level of 500 bands were examined, and at least 20 metaphase areas were evaluated. From the results of cytogenetic and FISH (fluorescence in situ hybridization) analysis, we determined the male had t(2;7)(p23;q35) chromosomal anomaly. The probe binding the patient’s 2p23 region signaled at the q-terminal of chromosome 7; however, the other two chromosomes (2 and 7) were normal. There is no report of such a case in the literature for recurrent pregnancy loss complaints. With this case, it will be reported for the first time that an embryo formed with the gametes carrying unbalanced genetic material of an individual with the karyotype 46, XY, t(2;7)(p23;q35) is incompatible with life.
Recurrent pregnancy loss is defined as pregnancy loss in a pregnancy lasting less than 20 weeks and repeated three times or more. Many factors can be the cause of recurrent pregnancy loss. Miscarriage occurs in 15% of pregnancies. In these cases, 1-2% of women suffer from recurrent pregnancy loss. However, most of them can achieve a healthy birth in their second or third pregnancies. Recurrent pregnancy loss occurs in 1 in 300 pregnancies.1
Among the causes of recurrent pregnancy loss are anatomical causes, genetic causes, environmental factors, uterine causes, and thrombophilic disorders. The most common cause of recurrent pregnancy loss is the deficiency or excess of one or more chromosomes. When examined proportionally, while it constitutes 70% of spontaneous abortions, chromosomal abnormalities occur in approximately 50% of recurrent pregnancy losses.2
Reciprocal translocations are structural chromosomal abnormalities and are common among chromosomal abnormalities. Reciprocal translocations constitute the genetic basis of 3% of families suffering from recurrent pregnancy loss.3 It has been reported that reciprocal translocations on chromosomes 1, 3, 7, 17, 19, and 22 lead to miscarriages.4 Although the individual with reciprocal translocation seems healthy, abnormal meiotic segregation may cause miscarriage. In this case report, t(2;7)(p23;q35) translocation in a male individual in a family presenting with recurrent pregnancy loss was identified by comparing cytogenetic and fluorescence in situ hybridization (FISH) analyses and recorded.
Case Presentation
A man, aged 32 years, presented with his wife due to recurrent pregnancy loss. Although the woman had been pregnant two times before, her pregnancies both ended in miscarriage. Neither the man nor the woman had any previously reported illnesses. The man’s parents also did not have a case of pregnancy that ended in miscarriage. Cytogenetic analysis was performed to check for the number of structural anomalies in the chromosomes of both the husband and the wife. Standard cytogenetic methods were used for karyotype analysis of the family. A 72-hour culture was performed using phytohemagglutinin (PHA)-induced peripheral blood lymphocytes. Metaphase preparations obtained after culture were stained with the Giemsa (GTG) banding method, and the chromosomes in the metaphase plate were evaluated in terms of structural and numerical irregularities. In addition to this test, chromosomes were also examined using the FISH method. For the FISH method, the CEP7 probe, which recognizes the centromere region of chromosome 7 and hybridizes to that region, was used. Cytocell brand ALK probe was used for the p23 region of chromosome 2. The obtained FISH data and cytogenetic data were compared. As a result of the analysis, it was observed that the male individual had a t(2;7)(p23;q35) balanced reciprocal translocation anomaly. No anomaly was found in the karyotype of the woman. Findings regarding the anomaly are shown in Figure 1 and Figure 2.
FISH image showing the 2p23 region translocated to the q35 region of chromosome 7.
Karyotype result of t(2;7)(p23;q35) anomaly seen in the case.
Discussion
In recurrent miscarriages, half of the cases are due to chromosomal abnormalities.5 In these cases, reciprocal translocations can form unbalanced gametes, and the pregnancy thus results in spontaneous abortus. These translocations can be of both paternal and maternal origin, but it has been determined that they are often of maternal origin.6 However, the embryo formed by these unbalanced gamete cells results in abortion due to defects in cell division and metabolism.
While gametes are formed in reciprocal translocation carriers, chromosomes with balanced reciprocal translocations during meiosis are paired with the homologous segment, forming a quadrivalent shape. In alternate segregation, both normal and balanced gametes are formed. Partial monosomic or partial trisomic gametes with unbalanced chromosomes occur in adjacent 1, adjacent 2 segregations. Completely unbalanced gametes are produced in 3:1, 4:0 type separations.6 In reciprocal translocations, there is always a risk of carriers forming unstable gametes. Therefore, as seen in this case, the separation type may present a reason for spontaneous abortions, but there is also the possibility of the family having healthy children.
There are about 2000 genes in the human chromosome 2 (“atlasgeneticsoncology”). There are 13 genes known to encode the protein localized in the 2p23 region (“atlasgeneticsoncology”). One of these genes is the LBH (limb-bud and heart) gene. This gene is intensely expressed in the heart, especially in the 17th to 25th week of the embryo. It acts as a transcriptional activator of cardiac gene expression.7 In cases of partial monosomy or trisomy, the regulatory activity of this gene may be lost, and the pregnancy may result in spontaneous abortion.
YPEL5 (Yippee-like 5) gene, located in the same region, is an important regulatory protein involved in the cell cycle.8 Fluctuations in the level of the protein produced from this gene may also have resulted in miscarriage. CAPN14 (calpain-14) is one of the important regulatory proteins of cytoskeletal dynamics and is localized in the 2p23 region.9 Partial deficiency or excess of this gene can be an example of another gene that is incompatible with life. There are 31 genes localized in the 17q35 region. Among these genes, CNTNAP2 (contactin-associated protein-2) is a member of the neurexin family and especially plays an important role in cell adhesion.10 Monosomy or trisomy of this protein may have caused abortus. In this case, it has been shown that genes that are very important for embryo development are encoded in both 2p23 and 7q35 regions.
No metabolic or hormonal imbalance was detected in our patient. It was explained to the patient that the gametes of the translocation in the father may segregate unevenly and cause miscarriage. To prevent the uneven distribution of this translocation to gametes, invasive and non-invasive prenatal genetic diagnostic tests were mentioned and recommended. In addition, preimplantation genetic diagnosis is recommended for carriers of reciprocal translocations as an alternative approach to prenatal diagnosis and termination of pregnancy of unbalanced fetuses. In this way, it is aimed to reduce the number of spontaneous abortions.
Due to the unbalanced chromosomal anomaly of parents with this anomaly, it constitutes an important group among prenatal cytogenetic diagnosis indications. This reveals the necessity of prenatal cytogenetic diagnosis in all subsequent pregnancies of parents with the reciprocal translocation.
Conclusion
In this case, it is predicted the differences that may occur in the expression of some of the genes located in the translocation region (described previously in the Discussion section) detected in a male individual in a family suffering from recurrent pregnancy loss, due to their important regulatory effects, especially in the developmental stage, may cause pregnancy loss. We emphasize that the genes mentioned above are important candidates that are worth investigating in cases of recurrent pregnancy loss.
Acknowledgements
We thank the family for allowing us to share this case.
Footnotes
Disclosure: The authors declare no conflicts of interest and that this study has received no financial support. Written informed consent was obtained from the family.
Author Contributions
AY applied the method and conducted research on the subject and provided the writing of the article. DT and RA researched the subject and gathered information about methodology. RA contributed both to the writing of the article and its revision. MD checked all processes and reviewed the article. All the authors read and approved the final manuscript.
- Received May 17, 2022.
- Revision received January 31, 2023.
- Accepted February 22, 2023.
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