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 included 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 Robertson translocation), a tetravalent (reciprocal), or a monovalent (homologous Robertson translocation)[13, 14], thus allowing the production of gametes of various types with different chromosomal components. In theory, 14 kinds of gametes can be produced by mutual translocation, and 6 kinds of gametes can be produced by non-homologous Robertson translocation. Among the gametes carried by these two types of carriers, only 1 kind of normal gametes, 1 kind of balanced translocation, and the rest are unbalanced gametes[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 the case, the three pregnancies of the women had similar genotypes and CNVs, and the defects showed a certain similarity, which suggested that the pregnancy outcomes for carriers with balanced translocations occured repeatedly, and the manifestations of the defective children show some similarity, which implies the similarity of their abnormal karyotypes. The preference for the formation of an abnormal product in meiosis may be related to the specific chromosome involved in translocations and the location of the fracture points[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 pregnant 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. The size of the deletion associated with 5p deletion syndrome ranges from 5 to 40 Mb[16]. 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 pregnant women'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 10.86 Mb region deletion at p15.33-p15.2. 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[17]. This gene encodes a protein which plays a critical role in neural development, particularly in the formation and maintenance of dendritic spines and synapses[18].
Duplication/trisomy of 4q has been reported in several patients since it was first described in 1972[19], 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[20]. 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[21]. In this case, the three pregnacies of a pregnant woman repeated the 24.16 Mb region at chromosome 4 q32.3-q35.2. 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, the CNV test results of the three pregnancies of the pregnant woman indicated a repeat of a 24.16 Mb at 4q32.3q35.2, belonging to 4q-terminal repeat. This region is known to cause disease. 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.
Because abnormal chromosomal structure can affect the normal division of germ cells, the risk of recurrence of fetal malformations or miscarriages in patients who are pregnant again is still high[22, 23]. Although second-trimester ultrasound abnormalities and abnormal maternal serum markers associated with 5p deletion syndrome have been reported[2, 24–30], there are no common abnormalities and it is difficult to prenatally identify 5p deletion syndrome[29]. In this case, the woman did not have a prenatal diagnosis because the ultrasound showed no abnormalities during the second pregnancy. As a result, the child had some diseases caused by chromosomal deletion or duplication. In our opinion, these pregnant women should actively cooperate with prenatal diagnosis to reduce the risk of birth of children with abnormal chromosomes. If necessary, assisted reproductive technology and preimplantation diagnosis can be selected[31].
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 if economic conditions permit[32]. 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.