Complex chromosomal rearrangements are very rare in the general population. Researchers had proposed many classification methods for CCRs according to the significance and impact of CCRs . In general, tripartite rearrangement CCRs accounted for the majority, followed by double reciprocal translocation CCRs, and both generally involved only chromosomal translocations. There were usually multiple breakpoints in special CCRs, and CCRs could produce multiple derivative chromosomes. They often involved chromosomal translocations and accompanied by structural abnormalities such as chromosomal inversions, insertions, and deletions. The case reported in this article was the only case with as many as 13 breakpoints, including special CCRs with reciprocal translocations, inversions, insertions and deletions reported to date in the literature. These involved structural abnormalities on the four chromosomes 6, 11, 16, and 18.
The mechanism of CCRs is very complex, and it has not yet been fully characterized. Studies had reported that the rearrangement of chromosomal structure was essentially due to double-strand breaks (DSBs) and double-strand break repair . A variety of endogenous and exogenous factors could damage chromosomes and caused DNA double-strand breaks including but not limited to ionizing radiation, radiotherapy, chemotherapy, free radical damage, and viral infection . The failure to repair double-strand breaks in time may be the direct cause of chromosomal structural rearrangement. The occurrence of CCRs is random, involving multiple fracture points and multiple regions. A single fractural rearrangement cannot produce CCRs. Pellestor et al.  has proposed that the formation of CCRs was likely not caused by simple gene point mutations, but by the structural characteristics of the genome. In this case of special CCRs, there was no clear radioactivity, drug, chemical exposure history, nor history of bacterial virus infection and other exogenous in-utero toxic exposure. Other members of the family had no abnormal chromosomal structure, and thus the cause of proband’s complex CCRs was unclear.
In this study, relying on traditional cytogenetic analysis techniques, we identified 6q abnormality, chromosome 11 inversion, reciprocal displacement of chromosomes 16 and 18, and 18q abnormality. However, due to the low resolution of this technology and the inability to distinguish similar bands, it cannot accurately characterize the complete karyotype abnormalities of CCR carriers. In order to further clarify the genetic aberrations, we performed fluorescence in situ hybridization analysis of subtelomere probes related to chromosomal abnormalities based on conventional karyotype analysis. The results showed t(6q;11p), t(16q;18p), but the specific form of 18q abnormality was still not clear. According to the results of high-throughput sequencing of the whole genome, it was found that the chromosome structure variation was very complicated, not only t(6q;11p)inv(11), t(16q;18p), but also some unresolved or unrecognized aberrations in G banding or FISH detection and analysis, such as partial deletion of 6q, and partial insertion of chromosome 18 and 11 into the long arm of chromosome 6. The same chromosome 18 has both inter-arm inversion and intra-arm inversion, specifically involving chromosome 6, 11, 16 and 18. There were 13 breakpoints, and the types of distortion included reciprocal translocation, intra-arm inversion, inter-arm inversion, insertion, deletion and so on. The complex rearrangements between chromosomes 6, 11, 16, and 18 involved the breaks of PLA2G15, DLG2, DLGAP1-AS5, and CTIF genes. Genetic diseases associated with these genes had not been included in OMIM. There was about 2.2M deletion in the q22.31 region of chromosome 6, involving 8 genes (ATP5LP2, CLVS2, FABP7, NKAIN2, PKIB, RN7SL564P, SMPDL3A, and TRDN). The TRDN gene was related to autosomal recessive catecholamine-sensitive ventricular tachycardia type 5 with or without myasthenia (OMIM:615441), but it was generally caused by homozygous or compound heterozygous mutations. No spontaneous abortion has been reported for the involved gene mutations. Although about 70% of CCR carriers did not have any clinically evident phenotype in the population test, they often caused many problems give rise on infertility, such as azoospermia, oligospermia, infertility, recurrent miscarriage, embryonic abortion, stillbirth, birth of congenital multiple deformities. Among them, the incidence of spontaneous abortion and embryo abortion was the highest. Madan et al. , Gorski et al.estimated that the incidence of spontaneous abortion and embryonic abortion in CCR carriers was about 50%. Studies by Yaping Liao  and Peng Dai et al. showed that the incidence of spontaneous abortion and embryo abortion were 77.6% and 81.6%, respectively, which was significantly higher in China than the rest of the world. Although the pregnancy outcome may vary greatly depending on ethnicities and geographic locations, studies worldwide had shown that the risk of abnormal pregnancy in CCRs carriers was extremely high. Special complex carriers of CCR had the highest risk of spontaneous abortion and embryo abortion. In the patients involved in this study, 4 natural conceptions were aborted in twelve weeks. The main reason was that the patient's chromosomes involved complex chromosomal rearrangements with multiple chromosomes, multiple sites, and multiple types of aberrations. During the meiosis process of egg formation in this patient, the probability of forming normal or balanced gametes was extremely low after the 4 chromosomes involved in structural rearrangement undergo pairing between homologous chromosomes and after meiosis. Most of them would form partial monomers or partial trisomy or even more complex unbalanced gametes, leading to early miscarriage, embryonic abortion, and stillbirth after fertilization. The probability that the patient could naturally give birth to normal offspring was extremely low. Although the rapid development of third-generation IVF assisted reproductive technology in recent years could help CCR carriers with low fertility to give birth successfully[20–25], the probability of obtaining normal or balanced embryos was very low and expensive. It may cause great harm to the patient and his family both physically and mentally. At this stage, if conditions permit, egg donation or adoption may be more realistic.