|Year : 2019 | Volume
| Issue : 2 | Page : 124-127
47,XYY,dup(13q12.11),t(4;9)(q21.1;q22.3),r(21)(p12q22.3) with azoospermia and low intelligence
Chao Lou, Han-Zhi Wu, Cui-Yun Qin, Shu-Wen Xin, Qiu-Hua Wu, Hong-Min Yan, Rong Qiang
Department of Genetics, Northwest Women's and Children's Hospital, Xi'an 710061, China
|Date of Submission||08-Apr-2019|
|Date of Web Publication||9-Jul-2019|
Dr. Rong Qiang
Department of Genetics, Northwest Women’s and Children’s Hospital, 1616 Yanxiang Road, Xi’an 710061, China
Source of Support: None, Conflict of Interest: None
A 27-year-old patient with azoospermia and low intelligence was reported having a rare karyotype 47,XYY,dup(13q12.11),t(4;9)(q21.1;q22.3),r(21)(p12q22.3). Clinical genetic tests, including next-generation sequencing (NGS), karyotyping, fluorescence in situ hybridization (FISH), and azoospermia factor (AZF) microdeletions, were conducted. The results showed that (1) one copy of chromosome 21 lost a short arm and appeared as a marker, but subsequent detection confirmed that it was a ring 21; (2) there was a reciprocal translocation between chromosome 4 and chromosome 9; (3) NGS revealed a duplication of 0.3 Mb on 13q12.11 and two Y chromosomes; (4) the Y chromosome showed no AZF microdeletions; and (5) FISH confirmed the two Y chromosomes. To our knowledge, this is the first reported case with rare karyotype, combined with four abnormal chromosomal changes simultaneously. Because no Online Mendelian Inheritance in Man genes were found in duplication fragment on 13q12.11, this duplication is not associated with low intelligence.
Keywords: Azoospermia; Ring Chromosome; Translocation
|How to cite this article:|
Lou C, Wu HZ, Qin CY, Xin SW, Wu QH, Yan HM, Qiang R. 47,XYY,dup(13q12.11),t(4;9)(q21.1;q22.3),r(21)(p12q22.3) with azoospermia and low intelligence. Reprod Dev Med 2019;3:124-7
|How to cite this URL:|
Lou C, Wu HZ, Qin CY, Xin SW, Wu QH, Yan HM, Qiang R. 47,XYY,dup(13q12.11),t(4;9)(q21.1;q22.3),r(21)(p12q22.3) with azoospermia and low intelligence. Reprod Dev Med [serial online] 2019 [cited 2019 Aug 20];3:124-7. Available from: http://www.repdevmed.org/text.asp?2019/3/2/124/262389
| Introduction|| |
Worldwide, 10%–15% married couples are sterile, with about 50% caused by male sterility., In China, 20% of sterile males have azoospermia, caused by many reasons, of which abnormal chromosome is the most important factor. Such abnormalities include translocation, inversion, isochromosome, and deletions on the Y chromosome. In our clinic, an azoospermia factor (AZF) microdeletion test is a necessary check for patients with azoospermia. AZF is located on chromosome Y q11.2, and in AZF, there are four nonoverlapping areas: AZFa, AZFb, AZFc, and AZFd. The chromosome rearrangement-driven deletions of AZFa, AZFb, and AZFb + AZFc can cause the total absence of sperms, as determined by testicular biopsy, but deletions in AZFc can only cause 55% azoospermia and 23% oligozoospermia. In the 47, XXY Klinefelter syndrome, the first reported abnormal karyotype of azoospermia, the testicles are as small as rice or beans, most seminiferous tubules atrophy or become fibrosis, and the ability to produce sperms is lost. With 47, XYY, most patients have no obvious symptoms, but the extra chromosome may lead to damage to seminiferous tubules, which causes azoospermia or oligozoospermia. As this patient had a complicated and rare karyotype, it is difficult to identify the specific reason leading to azoospermia.
| Case Report|| |
A 27-year-old male patient, with a height of 184 cm and a weight of 104 kg, showed good spirit, was fluent in language, and demonstrated low intelligence. He was found to be gentle and an introvert. His face looked normal; he had no less hair on forehead, had a normal distance between his eyes, and had a normal head size. His palms and fingers showed no apparent deformity [Figure 1]. His body and all four limbs were normal, with no O-leg formation or cross steps. Sperm was not found in the testicular biopsy performed at Xijing Hospital, Xi'an, owing to which he was diagnosed with azoospermia. The patient's parents denied exposure to radiation, chemical substances, and heavy metal pollution. We took blood samples from the patient and performed karyotype analyses, next-generation sequencing (NGS), karyotyping, fluorescence in situ hybridization (FISH), and AZF microdeletion test. In addition, the parents underwent karyotype analyses, and the results were normal.
Cytogenetic examination: The patient's samples were used for peripheral blood lymphocyte culture, production, and G-banding. By counting the 20 metaphase cells, and analyzing the three divisions, karyotype 47, XYY, dup(13q12.11), t(4;9)(q21.1;q22.3), r(21)(p12q22.3) was determined [Figure 2]. NGS result is shown in [Figure 3], FISH results are shown in [Figure 4], and the results of microdeletions on chromosome Y is shown in [Table 1].
|Figure 3: Next-generation sequencing. 13q12.11 (20960001–21260000) × 3.0, RefSeq Genes: IFT88, CRYL1, and MIR4499. Red: Deletion of chromosome fragment, Green: Duplication of chromosome fragment.|
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|Figure 4: In situ hybridization results (peripheral blood); (a) two chromosome 21 and two chromosome 13 – normal; (b) two chromosome Y, one chromosome X, and two chromosome 18 – extra chromosome Y. (a). Red: Chromosome 21, Green: Chromosome 13. (b). Red: Chromosome Y, Green: Chromosome X, Yellow: Chromosome 18.|
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| Discussion|| |
Reciprocal translocation is common in humans. Around 0.0283% of newborns have reciprocal translocations. However, most translocations occur between two chromosomes, and in theory, these translocations will produce 36 different gametes, and most of them will lead to abnormal chromosome recombination. In our case, there were two translocations between chromosome 4 and chromosome 9. Thus, it was difficult for the patient to have a normal baby, as most fetuses would be lost or spontaneously aborted., Unfortunately, the patient had two Y chromosomes and a ring chromosome 21. Although individuals with 47, XYY and ring chromosome 21 can produce sperm and even have children, most of their sperm carries abnormal chromosomes, making conception unlikely.
Patients with 47, XYY can have normal sperm development and conceive, but 47, XYY can also cause sperm deformity, lower sperm counts, and sperm abnormalities. However, it is less likely to cause azoospermia. In addition to the Y chromosome, multiple translocations may also affect sperm development. A balanced translocation of two chromosomes can produce 36 types of gametes, but the ratio of abnormal sperm to normal sperm will be much greater, leading to a higher deformity rate. However, it is uncertain whether this leads to azoospermia, and azoospermia may be more relevant to Y chromosome microdeletions, such as Y chromosome AZF, or the X chromosome's effect on the Y chromosome. Currently, while the effect of chromosomal translocation on azoospermia is not confirmed, there are reports, such as the one by Feng and Yang, that have found the condition t(Y; 4) with azoospermia. With the exception of Y chromosome translocation resulting in aberrant pairing between an abnormal sex chromosome and another chromosome, interference with the normal inactivation of spermatocytes in the pachytene period affects genetic regulation of sperm cell differentiation and causes azoospermia. At the molecular level, mutations in the AZF genes on the Y chromosome can affect the patient's sperm development and can also cause azoospermia. Recent studies have shown that a balanced translocation between autosomal chromosomes and a Robertsonian translocation may also contribute to spermatogenic failure.,, During a balanced translocation, most fault points are located on untranslated DNA regions, and thus, it has little effect on gene function, resulting in the normality of most carriers of this genomic phenotype. However, through studies on carriers' sperm morphology, penetration, chromosome composition, and information, many researchers have confirmed that balanced translocation has a negative effect on male fertility.
The 47, XYY syndrome was first discovered in 1961 by Sandberg. Records show that symptoms are not apparent in childhood, but appear in adulthood, perhaps due to strong and unbalanced hormone secretion. The intelligence quotient in adult patients is lower than average. Other symptoms include a violent temper, impulsive and aggressive behavior, muscular weakness, poor balancing ability, ataxia, and antisocial features, such as those found in criminals. Some patients can also have nodular acne and skeletal deformity, especially of the radioulnar joints. The sex characteristics are identical to those in healthy men. If the patient does not have a skeletal disorder, he can work freely and has no difficulty in climbing stairs. Surprisingly, the patient described here demonstrated an introverted and gentle temper and did not show obvious XYY behavioral characteristics, such as irritability and aggression. The patient was always submissive to his mother and had even served in the army, which made it difficult to believe that he was a 47, XYY patient. In general, 47, XYY patients are tall, and this case was not an exception, as he was 184 cm tall.
This patient also had a ring chromosome karyotype. Because of the ring chromosome's instability, it is easily lost in the process of cellular mitosis and meiosis. Interestingly, it can also produce a dicentric chromosome ring and even a double-ring chromosome, causing cellular ring mosaicism. In males, a ring chromosome can contribute to spermatogenic impairment. Most reported ring chromosomes show mosaicism, but in this patient, it did not, which is very unique. Ring chromosome 21 [R (21)] refers to the formation of circular chromosome reconnection of chromosome 21, and more than 80 cases have been reported thus far. Most R (21) cases are de novo mutations, and only a few have familial heritage.,, R (21) has many clinical and phenotypic variations, ranging from relatively mild phenotypes, in which individuals may be normal or only experience sterility or infertility, to severe deformities of various visceral organs or the presence of the trisomy 21 syndrome phenotype. Male ring chromosome carriers can also have spermatogenic disorders. Yanwei Sha investigated R (21) male patients and found testicular tissue damage, spermatogenic arrest, and the characteristics of azoospermia. It has been found that ring chromosomes 7, 11, 14, 15, 18, 20, 21, and 22 involve familial heritage, and patients with familial inheritance of a ring chromosome usually do not have distinct clinical phenotypes. In this case, the patient had azoospermia and no AZF microdeletions, and further research is required. We also found a duplication of 0.3 Mb on 13q12.11, but there were no Online Mendelian Inheritance in Man genes in this region; thus, this duplication is not associated with neural and intellectual development. We predict that it is not possible the duplication of 0.3 Mb on 13q12.11 can lead to low intelligence of this patient.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]