Microdeletions and vertical transmission of the Y-chromosome azoospermia factor region / 亚洲男科学杂志(英文版)

Spermatogenesis is regulated by several Y chromosome-specific genes located in a specific region of the long arm of the Y chromosome, the azoospermia factor region (AZF). AZF microdeletions are the main structural chromosomal abnormalities that cause male infertility. Assisted reproductive technology (ART) has been used to overcome natural fertilization barriers, allowing infertile couples to have children. However, these techniques increase the risk of vertical transmission of genetic defects. Despite widespread awareness of AZF microdeletions, the occurrence of de novo deletions and overexpression, as well as the expansion of AZF microdeletion vertical transmission, remains unknown. This review summarizes the mechanism of AZF microdeletion and the function of the candidate genes in the AZF region and their corresponding clinical phenotypes. Moreover, vertical transmission cases of AZF microdeletions, the impact of vertical inheritance on male fertility, and the prospective direction of research in this field are also outlined.

Reproductive outcomes of intracytoplasmic sperm injection using testicular sperm and ejaculated sperm in patients with AZFc microdeletions: a systematic review and meta-analysis / 亚洲男科学杂志(英文版)

Studies have explored the assisted reproductive technology (ART) outcomes of Y-chromosome azoospermia factor c (AZFc) microdeletions, but the effect of sperm source on intracytoplasmic sperm injection (ICSI) remains unknown. To determine the ART results of ICSI using testicular sperm and ejaculated sperm from males with AZFc microdeletions, we searched Embase, Web of Science, and PubMed to conduct a systematic review and meta-analysis. The first meta-analysis results for 106 cycles in five studies showed no significant differences in the live birth rate between the testicular sperm group and the ejaculated sperm group (risk ratio: 0.97, 95% confidence interval [CI]: 0.73-1.28, P = 0.82). The second meta-analysis of 106 cycles in five studies showed no difference in the abortion rate between the testicular sperm group and ejaculated sperm group (risk ratio: 1.06, 95% CI: 0.54-2.06, P = 0.87). The third meta-analysis of 386 cycles in seven studies showed no significant difference in clinical pregnancy rates between the testicular sperm group and the ejaculated sperm group (risk ratio: 1.24, 95% CI: 0.66-2.34, P = 0.50). Inevitable heterogeneity weakened our results. However, our results indicated that testicular sperm and ejaculated sperm yield similar ART outcomes, representing a meaningful result for clinical treatment. More properly designed studies are needed to further confirm our conclusions.

Prevalence of Y chromosome microdeletion in azoospermic infertile males of Iraqi population

In human gamete development, the important period is spermatogenesis, which is organized by specific genes on Y chromosome. In some cases, the infertile men have shown microdeletions on Y chromosome, which seemed as if the structural chromosome variance is linked to the reduction of sperm count. This study aimed to determine the frequency and patterns of Y chromosome microdeletions in azoospermia factor (AZF) of Iraqi infertile males. Here, 90 azoospermic infertile males as a study group and 95 normal fertile males as control group were investigated for the microdeletion of AZF loci using numerous sequence-tagged sites. Of these 90 infertile male patients, 43 (47.8%) demonstrated Y chromosome microdeletions, in which AZFb region was the most deleted section in azoospermia patients (33.3%) followed by deletions in the AZFc region (23%), while there were no microdeletion in the AZFa region. The largest microdeletion involved in both AZFb and AZFc was detected in six azoospermic patients (6.7%). The present study demonstrated a high frequency of Y chromosome microdeletions in the infertile Iraqi patients which is not reported previously. The high frequency of deletions may be due to the association of ethnic and genetic factors. PCR-based Y chromosome screening for microdeletions has a potential to be used in infertility clinics for genetic counselling and assisted reproduction.

The association between the two more common genetic causes of spermatogenic failure: a 7-year retrospective study / 亚洲男科学杂志(英文版)

Chromosomal abnormalities and Y chromosome microdeletions are considered to be the two more common genetic causes of spermatogenic failure. However, the relationship between chromosomal aberrations and Y chromosome microdeletions is still unclear. This study was to investigate the incidence and characteristics of chromosomal aberrations and Y chromosome microdeletions in infertile men, and to explore whether there was a correlation between the two genetic defects of spermatogenic failure. A 7-year retrospective study was conducted on 5465 infertile men with nonobstructive azoospermia or oligozoospermia. Karyotype analysis of peripheral blood lymphocytes was performed by standard G-banding techniques. Y chromosome microdeletions were screened by multiplex PCR amplification with six specific sequence-tagged site (STS) markers. Among the 5465 infertile men analyzed, 371 (6.8%) had Y chromosome microdeletions and the prevalence of microdeletions in azoospermia was 10.5% (259/2474) and in severe oligozoospermia was 6.3% (107/1705). A total of 4003 (73.2%) infertile men underwent karyotyping; 370 (9.2%) had chromosomal abnormalities and 222 (5.5%) had chromosomal polymorphisms. Karyotype analysis was performed on 272 (73.3%) patients with Y chromosome microdeletions and 77 (28.3%) had chromosomal aberrations, all of which involved sex chromosomes but not autosomes. There was a significant difference in the frequency of chromosomal abnormalities between men with and without Y chromosome microdeletions (P< 0.05).

Y chromosome microdeletion screening using a new molecular diagnostic method in 1030 Japanese males with infertility / 亚洲男科学杂志(英文版)

The azoospermia factor (AZF) region is important for spermatogenesis, and deletions within these regions are a common cause of oligozoospermia and azoospermia. Although several studies have reported this cause, the present research, to the best of our knowledge, is the first large-scale study assessing this factor in Japan. In this study, 1030 male patients with infertility who were examined for Y chromosome microdeletion using the polymerase chain reaction-reverse sequence-specific oligonucleotide (PCR-rSSO) method, a newly developed method for Y chromosome microdeletion screening, were included. The study enrolled 250 patients with severe oligospermia and 717 patients with azoospermia. Among the 1030 patients, 4, 4, 10, and 52 had AZFa, AZFb, AZFb+c, and AZFc deletions, respectively. The sperm recovery rate (SRR) of microdissection testicular sperm extraction in patients with AZFc deletions was significantly higher than that in those without AZF deletions (60.0% vs 28.7%, P = 0.04). In patients with gr/gr deletion, SRR was 18.7%, which was lower than that in those without gr/gr deletion, but was not statistically significant. In conclusion, our study showed that the frequency of Y chromosome microdeletion in male patients in Japan was similar to that reported in patients from other countries, and SRR was higher in patients with AZFc deletion.

Familial Y chromosome microdeletion with pericentric inversion of chromosome 19 / 中华男科学杂志

Objective@#To investigate the familial cytomolecular genetics of an infertile male.@*METHODS@#We analyzed the clinical phenotypes and karyotypes of three males from the family of an infertile man, detected the sequence-tagged sites (STS) in the AZF deletions of the Y chromosome by multiplex polymerase chain reaction (PCR), and identified the target genes by multiplex ligation-dependent probe amplification (MLPA).@*RESULTS@#The karyotypes of the proband and his brother were 46, XY, inv (19) (p13.3q13.1) and that of his father was 46, XY. The three males were all carriers of AZFc deletion of the Y chromosome, and all found with the same reduction of the gene copy number in the AZFb and AZFc regions.@*CONCLUSIONS@#Combined use of karyotype analysis, Y chromosome STS PCR, and MLPA revealed the genetic causes of the male infertile family.

Genetic Screening for Chromosomal Abnormalities and Y Chromosome Microdeletions in 846 Infertile Korean Men

BACKGROUND: Chromosomal abnormalities are confirmed as one of the frequent causes of male infertility. The microdeletion of the azoospermia factor (AZF) region in the Y chromosome was discovered as another frequent genetic cause associated with male infertility. The aim of this study was to evaluate the frequency and type of chromosomal abnormalities and Y chromosome microdeletions in Korean infertile men. METHODS: A total of 846 infertile men with azoospermia and severe oligozoospermia were included for genetic screening. Cytogenetic analyses using G-banding and screening for Y chromosome microdeletions by multiplex PCR for AZF genes were performed. RESULTS: Chromosomal abnormalities were detected in 112 infertile men (13.2%). Of these, Klinefelter's syndrome was the most common (55.4%, 62/112), followed by balanced translocation including translocation between sex chromosome and autosome (14.3%), Yq deletion (13.4%), X/XY mosaicism with Yq deletion (12.5%), and XX male (4.5%). The overall prevalence of Y chromosome microdeletions was 9.2% (78/846). Most microdeletions were in the AZFc region (51.3%) with a low incidence in AZFa (7.7 %) and AZFb (6.4 %). Combined deletions involving the AZFbc and AZFabc regions were detected in 26.9 % and 7.7 % of men, respectively. Among the infertile men with Y chromosome microdeletions, the incidence of chromosomal abnormality was 25.6% (20/78). CONCLUSIONS: There was a high incidence (20.1%) of chromosomal abnormalities and Y chromosome microdeletions in Korean infertile men. These findings strongly suggest that genetic screening for chromosomal abnormalities and Y chromosome microdeletions should be performed, and genetic counseling should be provided before starting assisted reproductive techniques.

The low frequency of Y chromosome microdeletions in subfertile males in a Sinhalese population of Sri Lanka.

Aims: This study was designed to determine the prevalence of azoospermia factor (AZF) microdeletions on the Y chromosome in Sri Lankan Sinhalese infertile men with azoospermia and severe oligozoospermia. Settings and Design: The patient group was 207 karyotypically normal infertile Sinhalese males. Materials and Methods: The presence of 13 sequence-tagged site (STS) markers in the AZF region was tested using multiplex polymerase chain reaction (M-PCR). One hundred and twenty unselected men were also studied as a control group. Results: Three (1.5%) had classic Y chromosome microdeletions in the AZFc sub-region. Conclusions: These results suggest a much lower Y chromosome microdeletion frequency than previously thought, even among a strictly selected group of sub-fertile males in Sri Lanka.

Detection of Y Chromosomal Microdeletions in Patients with Spermatogenic Failure / 中国医科大学学报

Objective To explore the relationship between Y chromosomal microdeletions and chromosome karyotype,clinical phenotypes and sex hormone levels in patients with spermatogenic failure.Methods SRY gene,ZFY gene and 6 sequence-tagged-sites in AZFa,AZFb and AZFc were detected with multiplex polymerase chain reaction in 42 non-obstructive azoospermic and 39 severe oligozoospermic men.Results Ten cases (12.35%) of microdeletions were found in 81 non-obstructive azoospermic (6 cases) or severe oligozoospermic patients (4 cases).Among the 10 patients with Y chromosomal microdeletions, 1 had deletion of AZFa+AZFb+AZFc,2 AZFb+AZFc, 1 AZFb and 6 AZFc.Conclusion Microdeletions in the long arm of Y chromosome were associated with spermatogenic failure.Screening for Y chromosomal microdeletions in azoospermic or severe oligozoospermic patients should be of necessity and significance.

Detection of the Microdeletion on the Y Chromosome of Patients with Idiopathic Oligospermia or Azoospermia / 대한진단검사의학회지

BACKGROUND: It has been proposed that the long arm of the human Y chromosome contains AZF (the azoospermia factor), the gene or genes that control spermatogenesis. In this study, I detected microdeletions on the long arm of the Y chromosome and analysed the relationship between the microdeletion detected and the failure of spermatogenesis in the patients investigated. METHODS: In this study, I analyzed 35 infertile patients, including 21 azoospermia and 14 oligospermia. Genomic DNAs were isolated from peripheral blood samples. Each sample was examined for the presence or absence of the total 9 Y-DNA landmarks on the Y chromosome including those deleted in the azoospermia and Y-chromosome RNA recognition motif (RBM1), using the polymerase chain reaction amplification. RESULTS: I detected microdeletions on the long arm of the Y chromosome in 4 patients with azoospermia. All 4 samples with microdeletions of the Y chromosome were identified with microdeletions of multiple loci. The microleletion incidence was 2.9% for sY143 and 11.4% for other loci (sY152, sY153 and sY255). But, the microdeletion of RBM1 was not identified. CONCLUSIONS: Even though the microdeletion analysis of the Y chromosome was not fully performed, this report suggests the presence of microdeletions within the Y chromosome in patients with azoospermia, supporting the relationship between the chromosomal region involved and the process of sper-matogenesis.

Microdeletions of Y Chromosome in Infertile Korean Men and Correlation with Pathologic Presentation / 대한남성과학회지

PURPOSE: Microdeletions on the Y chromosome have been associated with infertile in men. The deletions cluster in three regions, named azoospermia factor (AZF): AZFa, AZFb and AZFc. It has been suggested that deletions in AZFa result in Type I Sertoli cell-only (SCO) infertility (no spermatogonia present), deletions in AZFb in spermatogenic arrest, and deletions in AZFc Type II SCO (some spermatogonia present with limited spermatogenesis). The purpose of this study was to determine the prevalence of Y chromosome microdeletions and to correlate of the pathologic presentation with specific deletions in infertile Korean men. MATERIALS AND METHODS: We analyzed 115 non-obstructive azoospermic (NOA), 30 obstructive azoospermic (OA), 30 severe oligospermic (sperm concentration <5 x 10(6)/ml) patients and 50 fathered men. We tested leukocyte DNA by PCR for the presence of STS markers, AZFa (sY84, 85, 86), AZFb (sY129, 134, 135, 143, RBM1) and AZFc (DAZ, sY242). The PCR results were confirmed by Southern hybridization and were investigated by SSCP analysis for DAZ gene muations. RESULTS: None of 30 OA and 50 fertile men had microdeletions, but 15 (13.0%) of the 115 NOA and 4 (13.3%) severely oligospermic patients had one or more microdeletions. Deletions involving only the AZFc region were found in 9 men (3 severe oligospermia, 4 spermatogenic arrest, 1 Type I SCO and 1 Type II SCO). Deletions involving only the AZFb were found in 4 (1 severe oligospermia and 3 spermatogenic arrest), and deletions involving only AZFa were found in 1 (Type I SCO). Also, deletions involving the AZFb and AZFc were found in 5 (2 severe oligospermia and 3 Type I SCO). CONCLUSIONS: The prevalence of Y chromosome microdeletion was 13.0% and 13.3% in NOA and severely oligo spermia patients. The earlier reported association with particular types of infertility was not confirmed. The region of the deletions does not correlate with severity of spermatogenic failure or the presence of visible sperm. Deletions involving more proximal regions of the Y chromosome (AZFa) seemed to be rare.

Relationship between Microdeletions on the Y Chromosome and Defect of Spermatogenesis / 대한불임학회지

OBJECTIVES: To estimate the frequency of Y chromosome microdeletions in the Korean population of infertile men and to evaluate the relationship between microdeletion on the Y chromosome and clinical phenotypes of infertile men with idiopathic azoospermia and oligozoospermia. MATERIALS AND METHODS: Genomic DNA was extracted from blood samples collected from 330 infertile men attending the Infertility Clinic at Samsung Cheil Hospital, Korea. Six sequence tagged sites (STSs) spanning the azoospermia factor (AZF) regions of the Y chromosome were amplified by polymerase chain reactions (PCRs). RESULTS: Microdeletions on Y chromosome were detected in 35 (10.6%) of the 330 infertile men. Most of the microdeletions (91.4%) involved AZFb or AZFc. The high incidence of microdeletions were found in AZFc region (57.1%), but the low in AZFa (8.6%) and AZFb (5.7%). Larger microdeletions involving two or three AZF regions were detected in 28.6% of cases. All patients (6 patients) with deletion of AZFa region showed no germ cell phenotypes, Sertoli cell only syndrome or Leydig cell hyperplasia in histopathologic examinations. CONCLUSION: Microdeletions on the Y chromosome, especially, at AZFc/DAZ regions may be the major cause of azoospermia and severe oligozoospermia. We suggest that idiopathic infertile men have genetic counselling and microdeletion analysis on the Y chromosome before IVF-ET and ART program.

Relationship between Microdeletions on the Y Chromosome and Defect of Spermatogenesis / 대한불임학회지

OBJECTIVES: To estimate the frequency of Y chromosome microdeletions in the Korean population of infertile men and to evaluate the relationship between microdeletion on the Y chromosome and clinical phenotypes of infertile men with idiopathic azoospermia and oligozoospermia. MATERIALS AND METHODS: Genomic DNA was extracted from blood samples collected from 330 infertile men attending the Infertility Clinic at Samsung Cheil Hospital, Korea. Six sequence tagged sites (STSs) spanning the azoospermia factor (AZF) regions of the Y chromosome were amplified by polymerase chain reactions (PCRs). RESULTS: Microdeletions on Y chromosome were detected in 35 (10.6%) of the 330 infertile men. Most of the microdeletions (91.4%) involved AZFb or AZFc. The high incidence of microdeletions were found in AZFc region (57.1%), but the low in AZFa (8.6%) and AZFb (5.7%). Larger microdeletions involving two or three AZF regions were detected in 28.6% of cases. All patients (6 patients) with deletion of AZFa region showed no germ cell phenotypes, Sertoli cell only syndrome or Leydig cell hyperplasia in histopathologic examinations. CONCLUSION: Microdeletions on the Y chromosome, especially, at AZFc/DAZ regions may be the major cause of azoospermia and severe oligozoospermia. We suggest that idiopathic infertile men have genetic counselling and microdeletion analysis on the Y chromosome before IVF-ET and ART program.

Microdeletions in the Azoospermia Factor Region on the Y Chromosome Long Arm of Males with Idiopathic Azoospermia / 대한비뇨기과학회지

PURPOSE: Idiopathic azoospermia is the most common cause of male infertility Recently, much efforts have been focused on possible genetic etiologies. Mutations in the region of the Y chromosome long arm(Yq), known as the azoospermia factor(AZF) region, have been suggested. In the present study, we analysed Korean azoospermic men with cytologically normal Y chromosomes to examine possible genetic variations In regions of Yq, known to be associated with impaired spermatogenesis. MATERIALS AND METHODS: A total of 63 idiopathic azoospermic subiects were examined. Other cases Included in this study are as follows; 13 subjects with oligospermia, 12 subjects with chromosomal anomalies(eleven 47XXY patients, one 46xx male) and 2 normal subjects. Genomic DNAs were isolated from peripheral blood samples. Each sample was examined for the presence or absence of a total of 28 Y-DNA landmarks in the Yq including DAZ and RBM. To facilitate the analysis, we adopted multiplex PCR where simultaneous amplification of several targets is possible in a single reaction. RESULTS: We detected deletions of small, interstitial portions of the Yq In a total of 14 azoospermia patients(22.2%). Deletion incidence were 14.3% for DAZ and 17.5% for other loci(sy157, sy153, sy127, sy109). But deletion of RBM was not detected. Multiple deletions were found in 4 subjects. One patient with 47XXY and one patient with 46xx male also showed multiple deletions. However, testis biopsies revealed diverse histologic appearances in these subjects. CONCLUSIONS: As other deletions than DAZ were also found within AZF region, it is possible that normal spermatogenesis may be regulated by more than one locus in the Y chromosome; thus, it has yet to be waited to correlate genetic causatives and testicular phenotypes.