Prenatal Diagnosis of Unbalanced Translocations in Recurrent Pregnancy Losses in Two Couples

Abstract

Unbalanced translocation is a type of chromosomal abnormality where a portion of one chromosome is attached to another chromosome, resulting in an imbalance in the genetic material. This can lead to adverse pregnancy outcomes in the form of recurrent pregnancy loss, developmental problems, or major structural anomalies, depending on the specific chromosomes and regions involved. This can happen de novo during gametogenesis or it can be inherited from a parent who carries a balanced translocation. For a couple where one partner is a carrier of balanced translocation, there is a need for a detailed genetic counseling regarding the ideal test to be done for diagnosis, options of assisted reproduction, and limitations of these tests. We aim to highlight these aspects through two case illustrations: a first couple who were carriers of balanced translocation and a second couple who had normal tests.

Keywords

balanced translocation - unbalanced translocation - genetic testing - genetic counseling - prenatal invasive testing

Introduction

Unbalanced translocation is an unequal sharing of genetic material between two chromosomes resulting in net loss or gain. The subsequent effects of this depend upon the chromosome involved, the number of genes involved, and their respective functions. About 2 to 4% of cases of recurrent pregnancy loss are caused by parental balanced chromosome rearrangement.[1] [2] It can also lead to global developmental delay, intellectual disability, or multiple malformations if the size of the aberration is large.[2] Unbalanced translocations can arise denovo or it can be inherited from one of the parents who is a carrier of balanced translocation. There are three possibilities of inheritance in such a couple: either they will produce offspring with normal karyotype or can carry balanced translocation like the parents or they are carriers of unbalanced translocation. There is a lot of information that should be shared with couples who are carriers of balanced translocation, including the genetic tests and their limitations, prenatal diagnosis, and options for assisted reproduction. Certain rearrangements between highly homologous regions at increased risk of recombination are seen with greater frequency in the general population. All the acrocentric chromosomes, along with chromosomes 4, 7, 3, 6, 11, 17, and 22, are usually involved in reciprocal translocation. We aim to highlight all these aspects with the help of two case illustrations involving chromosomes 3, 6, 4, and 7.

Case 1

A 28 year old lady presented in her fourth pregnancy, out of nonconsanguineous marriage, with a history of two previous miscarriages at 8 and 7 weeks, followed by one medical termination of pregnancy for multiple anomalies, namely, dilated fourth ventricle, hypoplastic cerebellar vermis, increased nuchal fold thickness, and complex cardiac anomaly. Neither a fetal autopsy was done nor was any genetic workup done for that fetus. In the current pregnancy at 13 weeks, nuchal translucency was more than 95th centile, cleft palate was present, and the fourth ventricle was dilated ([Fig. 1]).

Fig. 1 Increased nuchal edema, dilated fourth ventricle, and cleft palate detected at 12 weeks.

The patient underwent chorionic villus sampling and the karyotype was suggestive of unbalanced translocation from chromosome 4 to 7 ([Fig. 2]), resulting in additional material to chromosome 7 at band point q32 from chromosome 4 at band point q31.1.

Fig. 2 Derivative of chromosome 7 resulted from additional material to chromosome 7 at band point q32 from chromosome 4 in the first case.

Consequently, parental karyotype was done and the father was found to be the carrier of balanced translocation from long arms of fourth to seventh chromosomes ([Fig. 3]).

Fig. 3 Balanced translocation between long arms of chromosomes 4 and 7 in the father.

This couple underwent genetic counseling and was informed of approximately 20 to 50% risk of recurrence of pregnancy losses as well as congenital anomalies in each natural conception and was given options of assisted reproduction with either intrauterine insemination with donor sperm or in vitro fertilization (IVF) with preimplantation genetic testing for structural chromosomal rearrangements (PGT-SR). This technique analyzes the outer layer of embryos for chromosomal abnormalities before transfer into the uterus.[3] The pregnancy should be followed up for any anomalies even if PGT-SR is performed and must be referred for invasive diagnostic testing in case of abnormal findings.

Case 2

A 32 year old lady, G3P2L1, presented at 13 weeks of gestation out of a nonconsanguineous marriage, with an ultrasound diagnosis of increased nuchal translucency (>95th centile) and ductus venosus agenesis. Her first pregnancy was a term pregnancy delivered by cesarean section, and she had a healthy male baby. In her second pregnancy, fetal growth restriction was diagnosed at 34 weeks, and she delivered a 2.1 kg male baby by cesarean section that had dysmorphic features and failed to thrive. However, no genetic or metabolic workup was done for the baby. In the present pregnancy, chorionic villus sampling was done in view of raised nuchal translucency and ductus venosus agenesis to rule out aneuploidy. Chromosomal microarray results showed an unbalanced translocation between short arms of chromosomes 3 and 6 ([Table 1]).

Table 1 Chromosomal microarray in the CVS sample of case 2 showed an unbalanced translocation between short arms of chromosomes 3 and 6

Sl. no.	Type	Chromosome	Cytoband	Size (kbp)	CN state	Gene count	Genomic coordinates (ISCN 2016[6])	Classification
1	Loss	3	p26.3–p25.3	10,512	1	78	arr[GRCh38] 3p26.3p25.3 (20,214_10,531,931)x1	Pathogenic[a]
2	Gain	6	p25.3–p24.3	7,109	3	63	arr[GRCh38] 6p25.3p24.3 (156,975_7,265,822)x3	Pathogenic[a]

Abbreviation: CNV, copy number variation.

^a Pathogenic: The CNV has been classified based on the ACMG guidelines specified by Kearney et al.[7]

There was a loss of 10.5 Mb on chromosome 3, spanning from the p26.3 to p25.3 region and containing 78 genes resulting in distal 3p deletion. There was also a gain of 7.1 Mb on chromosome 6, spanning from p25.3 to p24.3 and containing 63 genes resulting in distal trisomy 6p. The pregnancy was terminated as the aberration was associated with significant disabilities and mental handicaps. The abortus had nuchal edema on gross appearance ([Fig. 4]). Subsequently, parental karyotype was done to rule out balanced translocation in parents, but it did not show any abnormality.

Fig. 4 Nuchal edema in the abortus (arrow).

Discussion

Unbalanced translocations can be detected during workup for recurrent pregnancy losses, recurrent anomalies in a couple, or if a parent is a known balanced translocation carrier. Karyotyping can reveal large genomic changes (>5 Mb), while chromosomal microarray analysis (CMA) can detect even smaller copy number variations (CNVs) across the genome. CMA also provides more precise information about exact breakpoints and the number of genes involved, which can help in correlating the loss with the phenotype.[4] [5]

The first couple had a history of two miscarriages and recurrent fetal anomalies. The specific genes involved in the unbalanced translocation between chromosomes 4 and 7 led to multiple structural anomalies like cerebellar hypoplasia, dilated fourth ventricle, heart defects, and cleft palate. The couple went for conventional karyotyping as they could not afford CMA. Thus, the exact number of affected genes could not be ascertained. The father was a carrier of the balanced translocation, putting the couple at 20 to 50% risk of an unbalanced translocation in each natural pregnancy.[1] [2] Therefore, the couple was given the following options for future conception:

• In the case of natural conception, there was up to 50% risk of adverse pregnancy outcome and the couple should undergo prenatal genetic testing to rule out unbalanced translocation in the fetus.

• In case of IVF with self gametes, PGT-SR must be offered to select embryos without unbalanced translocation before uterine transfer.

• The third option is assisted reproduction using donor gametes: intrauterine insemination/IVF using donor sperm if the male is a carrier of balanced translocation or IVF using donor eggs.

Genetic counseling should also include testing of extended family members for carrier status.

In the second case, the CMA of the chorionic villus sample identified the exact genes involved in the unbalanced translocation, allowing correlation between genotype and phenotype. The couple previously had a baby with dysmorphic features and early neonatal death, likely due to an unbalanced translocation, but without genetic testing, this could not be confirmed. The CMA reported a complex CNV with gain at the sixth and loss at the third chromosome at their terminal regions. This kind of complex CNV indicates the possibility of balanced translocation of size less than 4 Mb, which cannot be picked up by karyotype but can affect the pregnancies. The second very rare possibility is gonadal mosaicism, which cannot be detected by any genetic testing.

Conclusion

For couples with a balanced translocation, genetic counseling must include the type of genetic test, the need for prenatal genetic testing, and the option of PGT-SR in case of IVF conception. The best test to be offered to detect unbalanced translocation should be chromosomal microarray rather than conventional karyotype.

Conflict of Interest

None declared.

Informed Consent

A written informed consent was taken from the patient to submit her de-identified images.

All the authors have read and approved the final version of the manuscript.

• References

• 1 Campbell IM, Stewart JR, James RA. et al. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet 2014; 95 (04) 345-359
• 2 Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol 2009; 2 (02) 76-83
• 3 Shetty S, Nair J, Johnson J. et al. Preimplantation genetic testing for couples with balanced chromosomal rearrangements. J Reprod Infertil 2022; 23 (03) 213-223
• 4 Xu HB, Yang H, Liu G, Chen H. Systematic review of accuracy of prenatal diagnosis for abnormal chromosome diseases by microarray technology. Genet Mol Res 2014; 13 (04) 9115-9121
• 5 Wapner RJ, Martin CL, Levy B. et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 2012; 367 (23) 2175-2184
• 6 McGowan-Jordan J, Simons A, Schmid M. eds. An International System for Human Cytogenomic Nomenclature. Basel: S. Karger AG; 2016. . Available at: https://doi.org/10.1159/isbn.978-3-318-06861-0
• 7 Kearney H, Thorland E, Brown K. et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 2011; 13 (07) 680-685

Publikationsverlauf

Artikel online veröffentlicht:
30. April 2025