New mechanism of partial duplication and deletion of chromosome 8: A case report

Abstract

BACKGROUND

During meiosis, the recombination of homologous chromosomes produces some new heritable mutations, which are the basis of biological evolution and diversity. However, when there is pericentric inversion of chromosomes, unbalanced gametes will be formed in the process of germ cell meiosis.

CASE SUMMARY

A 23-year-old pregnant woman at 25 wk of gestation wanted to terminate her pregnancy due to fetal chromosomal abnormalities. She had no exposure to toxic or hazardous substances before and during pregnancy, no history of medication usage during pregnancy, and she underwent cystectomy of ovarian cysts in 2017. On the second day of the 16^th week of gestation, non-invasive prenatal testing showed chromosome 8 copy number variation. Following genetic counseling, her pregnancy was terminated.

CONCLUSION

Recombinant offspring chromosome is rarely seen when the inversion segment is shorter than one-third of the chromosome length. In terms of the mechanism of chromosome 8 duplication/deletion occurrence, attention should be paid to the production of unbalanced gametes by the pairing of homologous chromosome during meiosis, and the possibility of mitotic recombination exchange as well.

Core Tip: The mechanism of partial deletion/duplication at the end of chromosome 8 involves two prevailing theories: Parental chromosome 8 inversion producing unbalanced gametes, and a recombination hot spot of chromosome 8p. Although the recombination hot spot of chromosome 8q occurring during mitosis is rarely reported, it was confirmed in the present case. Non-invasive prenatal testing (NIPT) for copy number variation has been used, but 40% or less mosaic abnormalities cannot be detected by NIPT. When chromosome 8 partial deletion/duplication occurs, in addition to the unbalanced gamete production caused by parental chromosome 8 inversion, attention should be paid to the mechanism of spontaneous recombination in meiosis or mitosis.

INTRODUCTION

The occurrence of duplicated and deleted offspring chromosome ends is commonly triggered by the joint pairing of pericentric inversion of chromosomes and homologous chromosomes during the first stage of meiosis. If the joint pairing forms an inverted ring, four different gametes are theoretically produced, including one with a normal chromosome, one with an inverted chromosome, and the other two with both partial duplication and partial deletions; e.g., mother46,xx,inv(8)(p15q36), offspring: 46,xy,rec(8)dup p,inv(8)(p15q36)mat. Many factors seem to influence the production of recombinant chromosomes, such as the affected chromosome and involved region, location of the breakpoints, or size of the inverted segment. The rate of recombination varies according to the size of the inverted segment[1]. Research has shown that chromosome 8p has a recombination hot spot, which leads to the complex de novo 8p rearrangement[2,3].

CASE PRESENTATION

Chief complaints

A 23-year-old pregnant woman at 25 wk of gestation wanted to terminate her pregnancy due to fetal chromosomal abnormalities.

History of present illness

On the second day of the 16^th week of gestation, non-invasive prenatal testing (NIPT) showed chromosome 8 copy number variation.

History of past illness

The patient underwent a cystectomy for benign ovarian cysts in 2017.

Personal and family history

The patient had no special personal and family history.

Physical examination

The pregnant woman’s uterine height was 23 cm, abdominal circumference was 84 cm and blood pressure was 114/64 mmHg.

Laboratory examinations

NIPT showed that there was low-risk syndrome of chromosome 13, 18 and 21 and high risk of the end of the short arm of chromosome 8 missing about 3 Mb (Figure 1). Amniocentesis chromosome microarray analysis showed: arr[GRCH37]8p23.3p23.2 (158048-3220759)x1,8q21.11q24.3(77115706-146295771)x3 (Figure 2).

Figure 1.

Non-invasive prenatal testing showed high risk of 3 Mb deletion at the end of chromosome 8p.

Figure 2.

Amniocentesis chromosome microarray analysis showed 3.06Mb deletion in 8p23.3p23.2, and 69.18Mb duplication in 8q21.11q24.3.

Imaging examinations

Systematic ultrasonography showed that the fetal ventricles were widened bilaterally, and the measured value of the septum pellucidum was smaller than the normal. Cardiac ultrasound suggested fetal venous catheter occlusion or absence.

FINAL DIAGNOSIS

The fetus had an abnormal copy number of chromosome 8 and restricted placental mosaicism.

TREATMENT

The pregnancy was terminated after genetic counseling.

OUTCOME AND FOLLOW-UP

The couple underwent peripheral blood karyotype examination, and no significant abnormalities were seen in the G-dominant band (400 bands). They have no plans for another pregnancy.

DISCUSSION

In the present case, NIPT showed that the fetus may have a terminal deletion of chromosome 8p (Figure 1), and amniocentesis chromosome microarray analysis showed a deletion/duplication of chromosome 8p/8q (Figure 2). They are not consistent with each other. It has been reported that NIPT has higher efficiency for detecting > 2 Mb copy number variations[4-7] compared to other techniques. However, further placental high-throughput sequencing confirmed that the placental long-arm terminal duplication was 40% mosaic (Figure 3), indicating that NIPT may not have a high detection rate when chromosomal copy number variations show a low placental mosaic proportion, thus it has a limited role in the detection of chromosomal copy number variations.

Figure 3.

Placental high throughput sequencing showed 3.06Mb deletion in 8p23.3p23.2, and 69.18Mb duplication in 8q21.11q24.3 with 40% mosaicism.

All the chromosomes, mostly chromosomes 2 and 8, are known to be involved in pericentric inversions[8]. Carriers of these inversions can produce a significant percentage of chromosomal unbalanced gametes (duplication q/deletion p or duplication p/deletion q). The rate of recombination varies according to the size of the inverted segment[1,9].

Chromosome 8p is especially prone to various genomic rearrangements mainly due to the existence of the two olfactory receptor gene clusters (REPD and REPP) of 8p23.1[10-12].

In the present case, the chromosome microarray analysis indicated a deletion of 8p and a duplication of 8q, and pericentric inversions of chromosome 8 were not found in the couple’s G-dominant band (400 bands) of chromosomal karyotype (Figure 4). CNV-seq of the placenta indicated a deletion of 8p and a duplication of 8q with 40% mosaicism (Figure 3). All the above data indicated that the short-arm deletion and long-arm duplication of fetal chromosome 8 were new mutations. The deletion of chromosome 8p is presumed to have a high possibility of a deletion in the meiotic homologous chromosome synapsis and exchange, which is consistent with the high recombination rate of the terminal arm of chromosome 8 based on the database of recombination rates of human homologous chromosomes[3]. Cases of terminal deletion of chromosome 8p have also been reported[13,14], which further confirmed that mutation sites may be at the end of the short arm of chromosome 8 resulting in the prevention of breakpoints from synapsis and recombination. The duplication of chromosome 8q may arise from a disorder of the mitotic homologous chromosome recombination early in the development of the fertilized egg, and later the inner cell mass of the mulberry embryo develops from the deletion and repeated cell line of chromosome 8. Thus, two cell lines exist in the placenta resulting in the terminal deletion and duplication of chromosome 8p and chromosome 8q.

Figure 4.

The karyotype of the mother and father. A: The karyotype of the mother was 46,XX; B: The karyotype of the father was 46,XY.

CONCLUSION

Recombinant offspring chromosomes are rarely seen when the inversion segment is shorter than one-third of the chromosome length. The extent of the genetic imbalance of these recombinants depends on the relative size of the inversion segment. In terms of the mechanism of chromosome 8 duplication/deletion occurrence, attention should be paid to the production of unbalanced gametes by the pairing of homologous chromosome during meiosis, and the possibility of mitotic recombination exchange as well.