Balanced translocation carriers account for 0.08-0.3% of the normal population[9]. Balanced translocation is a common type of chromosomal abnormality. The carrier status of balanced translocation is associated with recurrent miscarriage and adverse pregnancy[10]. An obvious balanced translocation may result in a clinical phenotype by gene disruption or changed expression of genes in or around the breakpoint region[11]. Several researchers have proposed three hypotheses that including a break in a gene, positional effect, and cryptic deletion or duplication to explain such phenotype abnormalities[12].
Eggs from women with balanced translocations can show several types of nuclear contents: normal, balanced or unbalanced karyotype. For carriers of balanced translocations, the normal divalent structure of the germ cell in the first meiotic division will be replaced by a trivalent (non-homologous robertsonian translocation), a tetravalent (reciprocal), or a monovalent (homologous robertsonian translocation)[13, 14], thus allowing the production of gametes of various types with different chromosomal components. The balanced translocation carrier of two chromosomes can form a quadrivalent in meiosis, which can produce various gametes according to the different ways of segregation. There are three ways of segregation: 2:2(alternate segregation, adjacent-1 segregation and adjacent-2 segregation), 3:1, and 4:0. Taking into account the exchange of these three ways, a total of 36 gametes can be produced in theory. Studies have shown that the way of segregation of balanced translocation carriers is mainly 2:2, while 3:1 and 4:0 are rare[13, 14]. Due to the diversity and randomness of gametes' chromosome composition, the pregnancy outcomes of balanced translocation carriers vary greatly, not only among different translocation types, but also among the pregnancies of each carrier. In this case, the woman's three pregnancies had similar genotypes and CNV, indicating that the pregnancy outcome of the balanced translocation carrier may occur repeatedly. This suggested that the similarity of the abnormal karyotype and the preference for a certain abnormal product formed in meiosis may be related to the location of the fracture point[14, 15].
Distal deletions of 5p cause Cri-du-Chat syndrome (OMIM #123450) with a cat-like cry in infancy, dysmorphic facial features, microcephaly and intellectual disability. In the present case, clinical features of the woman’s son were characterized a high-pitched cat-like cry, developmental delay, severe psychomotor and mental retardation, which were consistent with Cri-du-Chat syndrome. Most 5p deletions are caused by new mutations, of which 80% ~ 90% come from the paternal line and are caused by chromosome breakage during gametogenesis[16]. In the case, the 5p terminal deletion was consistent in the woman's three pregnancies. The father of the fetus has a normal karyotype, so it is considered that the 5p deletion of the three fetuses are inherited from the mother's balanced translocation. This case of maternal inheritance of 5p deletion syndrome is clinically rare. The size of the deletion associated with 5p deletion syndrome ranges from 5 to 40 Mb[17]. The larger the deleted fragment, the more severe the patient's clinical symptoms.The clinical phenotype may be related to genes deleted on the short arm of chromosome 5. Surprisingly, the woman's three pregnancies we reported suggested partial deletion of short arm of chromosome 5. The results of the three pregnancies by CNV-seq indicated that chromosome 5 had a 10.86Mb region deletion at p15.2-p15.33. The deleted region encompasses 87% candidate genes of the Cri du Chat Syndrome (5p deletion). The critical region for the cat-like cry was mapped to a 1 Mb interval at 5p15.32 encompassing a candidate gene ICE1(OMIM *617958), which regulates small nuclear RNA transcription; the TERT(OMIM *187270) gene at 5p15.33 and the SEMA5A(OMIM *609297) and CTNND2(OMIM *604275) genes at 5p15.31p15.2 were considered candidate genes for autistic and cognitive phenotypes[18]. This gene encodes a protein which plays a critical role in neural development, particularly in the formation and maintenance of dendritic spines and synapses[19]. The gene may be linked to the child's developmental delay. In addition, a 0.34-Mb duplication at 1q41q42.11 and a 0.56-Mb duplication at 17p12 were found. We thought the duplication of these segment happen de novo. And no clear pathogenic information related to the fragments of Chromosome 1 and 17 has been found in public database resources to date. Therefore, the duplication regions of chrosome 1 and 17 were not associated with the child's phenotype.
Duplication/trisomy of 4q has been reported in several patients since it was first described in 1972[20], most of which resulted from the malsegregation of a familial translocation. Patients with dup4q syndrome have variable clinical features, which are both related to the size and gene content of duplicated segment and specific associated monosomy[21]. Usually, concomitant monosomy of another chromosome segment complicates the phenotype[5, 6].Elghezal et al. showed that segment 4q35 was probably involved in microcephaly, severe growth and mental retardation[22]. In this case, there was a 24.16-Mb duplication at 4q32.3-q35.2 in the woman’s three pregnacies. After a public database query, one case of 4q35 duplication was reported in the literature. The main clinical features are focal segmental glomerulosclerosis, bilateral sensorineural hearing loss, bilateral retinopathy, basal ganglia calcification, reflex myoclonus, retardation, etc. [PMID: 20191367]. In this case, all the CNV-seq results of the three pregnancies indicated a 24.16-Mb duplication of at 4q32.3q35.2. According to OMIM database, several pathogenic genes were contained at 4q32.3q35.2 including PALLD, TLL1, NEK1, HPGD, VEGFC, AGA and TENM3 and so on. These genes are associated with familial pancreatic cancer, short-rib thoracic dysplasia, enlargement of the nail plate and terminal segments of the fingers and toes, lymphatic malformation, aspartylglucosaminuria. In this case, the child does not currently have any symptoms mentioned above, but he needs further follow-up. Because abnormal chromosomal structure can affect the normal division of germ cells, the risk of fetal malformation or miscarriage remains high in patients in the following pregnancy.[23, 24]. Although ultrasound abnormalities in the second trimester and abnormalities in maternal serum markers have been reported to be associated with 5p deletion syndrome, 5p deletion syndrome has no characteristic changes in ultrasound and serum markers, so it is difficult to identify 5p deletion syndrome in the prenatal [2, 25-31]. In this case, because the ultrasound showed no abnormalities during the second pregnancy, the woman did not receive a prenatal diagnosis, resulting in some chromosomal deletions or duplications in the child. Balanced translocation couples may attempt to conceive naturally. Although the theoretical risk of spontaneous abortion is high for both carriers, many cases have produced offspring with normal phenotypes after genetic counseling in practice. Of course, prenatal diagnosis should be recommended after a natural pregnancy. From our point of view, if necessary, assisted reproductive technology and preimplantation diagnosis can be selected to reduce the risk of birth of children with abnormal chromosomes[32].
At present, for balanced translocation carriers, it is generally recommended to select preimplantation genetic diagnosis (PGD) to obtain offspring, which may be a best choice[33]. It should be noted that clinical genetic counseling should be conducted so that patients can fully understand the advantages and disadvantages of different fertility methods, as well as the risks involved. At the same time, the importance of prenatal diagnosis should be clarified and informed choices should be made.