Mammalian cells have two sex chromosomes, with males carrying the X and Y chromosomes and females carrying two X. Genes in X are much more abundant than those in Y. Dosage compensation is achieved by silencing one X to achieve equal dosages of XX and XY [9]. In early embryogenesis, one of the two X chromosomes in each female embryo cell is randomly deactivated, known as the Lyon hypothesis [10, 11]. In fact, only partial fractions on the inactivated X chromosome were deactivated and lack of transcriptional activity, on the other fractions some gene sites contain transcription and make double doses function, such as primary pseudoautosomal regions(PAR1)、secondary pseudoautosomal regions(PAR2) and a X-Y shared fragment about 4 Mb length located at Xq21.3 [12, 13]. Transcriptional silencing is initiated by an X chromosome inactivation center (XIC) located at Xq13. Which X chromosome will be deactivated is random [14]. If the derived/translocated X chromosome is deactivated, the gene silencing also spreads to the autosomal segment that is connected to it. This phenomenon may induce more phenotypic abnormalities [15, 16]. Theoretically, normal phenotype and gene function can only be achieved with normal X chromosome inactivation. So between normal X and derived/translocated X, which one is inactivated may determine whether a person is phenotypically normal or abnormal [11].
We report ten cases of X translocation. Abnormal reproductive system are observed in three cases. Case 1–3 are secondary amenorrhoea, infantile or small uterus, and absence or small ovaries. Extremely low levels of AMH indicate ovarian insufficiency. We discover the breakpoints on the translocation X located at Xq25, Xq13, and Xq21 (Fig. 1). Patients with X translocation and premature ovarian insufficiency(POI) constitute an interesting study on the location of breakpoints. The Xq critical region, known for its role in maintaining ovary function and normal reproductive lifespan, is located on the long arm of Xq13-q27 [17–19]. To investigate the effects of balanced X-autosome translocation resulting in POI, Di Battista fine-mapped breakpoints in six patients with POI and balanced X-autosome translocation and addressed the gene expression and chromatin accessibility changes in four of them. The results observe that translocation has a broad effect on the chromatin structure, suggesting that this study supports the hypothesis of positional effects as a causal mechanism for premature ovarian insufficiency associated with X-autosome translocation [20].
Case 4 and 5 are fertile females carrying normal growth and mental development. Ultrasound and hormonal evaluation show no abnormalities. The karyotype of the patients are established to be 46,X,t(X;5)(p22.3;q22) and 46,X,t(X;14;4)(q24;q22;q33), with a balanced translocation of X-autosome. In case 4, at 20 weeks’ gestation, ultrasound showed that the fetus had tetralogy of Fallot, intense left heart spot, single umbilical artery and small kidneys. Prenatal diagnosis from the amniotic fluid cells suggested that the karyotype of the fetus was 47,XN,+der(X)t(X;5)(p22.3;q32)mat, with a duplication of Xp22.3-pter and partial trisomy of 5q32-qter confirmed by chromosomal microarray (Fig. 2). The 5q trisomy phenotype is associated with heart, lungs, abdomen, limbs, and genitalia. The fetus of case 4 also had abdominal, limbs and cardiac malformations. In case 5, the patient with complex reciprocal translocation experienced early spontaneous abortion twice. These two cases reveal that the balanced translocation of the X-autosome may occur without significant detrimental phenotype due to normal X inactivation, but the carrier will face increased risks such as recurrent spontaneous abortion, stillbirths, and congenital disabilities in the resulting offspring [21]. In addition, unpredictable detrimental phenotype associated with skewed XCI patterns may occur in female carrier embryos, and azoospermia or severe oligospermia may occur in nearly all male carrier embryos [22, 23].
We also describe two cases of fertile women with an unbalanced translocation of X-Y, consisting of Xp22.3qter connected an additional chromosomal Yq11.2qter, which was detected by conventional G-banding studies. The G-banding chromosome karyotype is established to be 46,X,der(X)t(X;Y)(p22.3;q11.2) for case 6 and 7. Furthermore C-banding visualized heterochromatin ligated to the Xp22.3 (Fig. 3). Theoretically according to the breakpoints on Xp, patient would appear detrimental phenotype associated with the deletion of functional genes such as short stature homeobox(SHOX), arylsulfatase E, MRX49, NLGN4. The extra Y chromosome possesses Yq11.2-qter, excluding SRY [24]. Female carries of X-Y translocation are generally phenotypical normal and fertile as case 6 and 7. The pattern of X inactivated prefer to der(X)t(X;Y), which is variable and unpredictable. Males hemizygote with X-Y translocation would inevitably appear azoospermia for the reason that spermatogenic arrest caused by disruption of the formation of the sex vesicles [25, 26]. For case 7 the karyotype and Copy Number Variation Sequencing (CNV-seq) of amnio fluid cells reveal that the male fetus is 46,Y,der(X)t(X;Y)mat which inherited der(X) from maternal origin. The fetus appeared short limbs for the haploinsufficiency of SHOX associated with Leri-Weill dyschondrosteosis (LWD).
Case 8-10 are male patients who was admitted to our hospital for primary infertility. They underwent chromosome karyotype and semen analysis. G-banding karyotype revealed a balanced reciprocal translocation of chromosome X and autosome (1,3 and 8) (Fig. 4). Multiple semen analyze confirmed no sperm, and endocrine evaluation was normal. Y chromosome microdeletion analysis revealed that sex determining region of Y-chromosome(SRY), azoospermia factors a, b and c(AZFa, AZFb and AZFc) were present. Chromosomal abnormality is a primary genetic factor that leads to azoospermia and male infertility. Even if the copy number of cellular chromosome is balanced, almost all hemizygous males with X-autosomal translocations are infertile [27]. Choi reported a 26-year-old male presenting for initial infertility evaluation, a detailed physical exam and laboratory tests were normal except for an abnormal karyotype with a reciprocal translocation at chromosomes X and 16. An open testicular biopsy demonstrated 75% late maturation arrest at the spermatid stage, without evidence of significant peritubular fibrosis or hyalinization on pathology which confirming reproductive potential although significantly reduced. With immature sperm on testicular biopsy, the carries may be candidate for testicular excisional sperm extraction with intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) [28, 29].