Evaluation from a different perspective of 10-year results of infertile males with Y chromosome AZFc microdeletions compared with a control group.

AZFc microdeletions will be evaluated upon being divided into partial and complete subgroups. The association of deletions with reactive oxidative stress (ROS) and sperm DNA fragmentation (SDFI) and the impact of their coexistence on fertility starting from the pregnancy process until live birth will be presented. Semen analyses, microbiological results, hormones, ROS and sperm TUNEL tests were checked. Preimplantation genetic testing (PGT) was planned for relevant patients. Intracytoplasmic sperm injection (ICSI) was applied. Their embryo fragmentation was monitored via time lapse. Their results were compared with those with no AZF deletion and no other genetic problems. Azoospermia rate was 71.5%, m-TESE success rate was 25%, pregnancy rate was 26% and live child rate was 2.2%. No difference was detected between the partial and total groups in terms of ROS and SDFI rates and no difference was identified with the control group. Better results were obtained in terms of live child rate in patients with partial AZFc and low ROS/SDFI. Spermatozoon was retrieved in AZFc deletions and pregnancy, and live child was identified. No AZFc impact was observed on ROS and SDFI in the results compared with the control groups in terms of their coexistence.

AZF deletions in Indian populations: original study and meta-analyses.

PURPOSE: To identify the frequency of Y chromosome microdeletions in Indian populations and to quantitatively estimate the significance of association between these deletions and male infertility. METHODS: A total of 379 infertile males (302 azoospermic and 77 oligozoospermic infertile males) and 265 normozoospermic fertile males were evaluated for Y chromosome microdeletions (YCD) using PCR amplification and gel electrophoresis. Meta-analyses were performed on AZFa (2079 cases and 1217 controls), AZFb (2212 cases and 1267 controls), AZFc (4131 cases and 2008 controls), and AZFb+c (1573 cases and 942 controls) deletions data to quantitatively estimate the significance of association between these deletions and male infertility in Indian populations. RESULTS: The results revealed that out of 379 infertile azoospermic and oligozoospermic males, 38 (10.02%) had AZF deletions. No deletion was found in control samples. The highest percentage of deletions was observed in the AZFc region, followed by AZFa and AZFb. Qualitative analysis showed that AZF deletions were present in 0.59 to 32.62% (average 13.48%) of infertile cases in Indian populations. Meta-analysis revealed a significant association of AZFa (OR = 6.74, p value = 0.001), AZFb (OR = 4.694, p value = 0.004), AZFc (OR = 13.575, p value = 0.000), and AZFb+c (OR = 5.946, p value = 0.018) deletions with male infertility. CONCLUSION: AZF deletions were seen in 10.02% of azoospermic and oligozoospermic cases with the highest frequency of AZFc deletions. Pooled analysis for all studies showed deletion frequency from 0.59 to 32.62% (average = 13.48%). Meta-analysis showed significant association of AZFa, AZFb, and AZFb+c deletions with male infertility. Analysis of Y chromosome microdeletions should be reckoned as an essential testing for diagnostic and therapeutic purposes.

Sex chromosomes-linked single-gene disorders involved in human infertility.

Human infertility is a healthcare problem that has a worldwide impact. Genetic causes of human infertility include chromosomal aneuploidies and rearrangements and single-gene defects. The sex chromosomes (X and Y) are critical players in human fertility since they contain several genes essential for sex determination and reproductive traits for both men and women. This paper provides a review of the most common sex chromosomes-linked single-gene disorders involved in human infertility and their corresponding phenotypes. In addition to the Y-linked SRY gene, which mutations may cause XY gonadal dysgenesis and sex reversal, the deletions of genes present in AZF regions of the Y chromosome (DAZ, RBMY, DBY and USP9Y genes) are implicated in varying degrees of spermatogenic dysfunction. Furthermore, a list of X-linked genes (KAL1, NR0B1, AR, TEX11, FMR1, PGRMC1, BMP15 and POF1 and 2 regions genes (XPNPEP2, POF1B, DACH2, CHM and DIAPH2)) were reported to have critical roles in pubertal and reproductive deficiencies in humans, affecting only men, only women or both sexes. Mutations in these genes may be transmitted to the offspring by a dominant or a recessive inheritance.

TBL1Y: a new gene involved in syndromic hearing loss.

Hereditary hearing loss (HHL) is an extremely heterogeneous disorder with autosomal dominant, recessive, and X-linked forms. Here, we described an Italian pedigree affected by HHL but also prostate hyperplasia and increased ratio of the free/total PSA levels, with the unusual and extremely rare Y-linked pattern of inheritance. Using exome sequencing we found a missense variant (r.206A>T leading to p.Asp69Val) in the TBL1Y gene. TBL1Y is homologous of TBL1X, whose partial deletion has described to be involved in X-linked hearing loss. Here, we demonstrate that it has a restricted expression in adult human cochlea and prostate and the variant identified induces a lower protein stability caused by misfolded mutated protein that impairs its cellular function. These findings indicate that TBL1Y could be considered a novel candidate for HHL.

Analysis of partial azoospermia factor c deletion and DAZ copy number in azoospermia and severe oligozoospermia.

Microdeletions of the azoospermia factor (AZF) regions in the Y chromosome are a well-known genetic cause of male infertility, resulting in impairment of spermatogenesis. However, the partial deletions of AZFc region related to spermatogenetic impairment are controversial. We investigated partial deletion of AZFc region and DAZ copy number in a population of Iranian infertile men and normozoospermic controls. In total, 154 infertile men (113 patients with azoospermia, 41 with oligozoospermia) and 111 normozoospermic controls were analysed using PCR. Gene dosage analysis of the DAZ genes was performed by fragment analysis. Our results showed that the frequencies of gr/gr deletion in the azoospermic, severe oligozoospermic and normozoospermic men were 4.4% (5/113), 7.3% (3/41) and 1.8% (2/111) respectively. In the azoospermic patients, the frequency of b2/b3 was 1.8% (2/113). Partial AZFc deletions were not significantly different between the infertile and normozoospermic men. The frequencies of gr/gr deletions and b2/b3 were not significantly different between the azoospermic/severe oligozoospermic men and normozoospermic controls. Our data suggested that gr/gr deletion was not associated with azoospermia/oligozoospermia in an Iranian population.

Susceptibility of gr/gr rearrangements to azoospermia or oligozoospermia is dependent on DAZ and CDY1 gene copy deletions.

PURPOSE: The purpose of this study was to determine the association of AZFc subdeletions (gr/gr, b1/b3 and b2/b3) and deletion of DAZ and CDY1 gene copies with male infertility METHODS: Three hundred twelve controls, 172 azoospermic and 343 oligozoospermic subjects were subjected to AZFc subdeletion typing by STS PCR. Deletion of DAZ and CDY1 gene copies was done using sequence family variant analysis. Sperm concentration and motility were compared between men with and without AZFc subdeletions. Effect of the AZFc subdeletions on ICSI outcome was evaluated. RESULTS: Amongst the three AZFc subdeletions, the frequency of gr/gr was higher in oligozoospermic (10.5 %) and azoospermic (11.6 %) men as compared to controls (5.1 %). In men with AZFc subdeltions, loss of two DAZ and one CDY1 gene copy made them highly susceptible to azoospermia and severe oligozoospermia with OR of 29.7 and 26, respectively. These subdeletions had no effect on ICSI outcome, albeit there were an increased number of poor quality embryos in AZFc subdeleted group. CONCLUSION: AZFc subdeletions are a major risk factor for male infertility in the Indian population. In the subjects with AZFc subdeletions, the deletion of DAZ and CDY1 gene copies increases its susceptibility to azoospermia or severe oligozoospermia. Since these deletions can be vertically transmitted to the future male offspring by ICSI, it will be essential to counsel the couples for the transmission of the genetic defect in the male offspring born after assisted reproduction and the risk of perpetuating infertility in future generation.

Screening for AZFc partial deletions in Dravidian men with nonobstructive azoospermia and oligozoospermia.

CONTEXT: Dravidians are the predominant population residing in South India with a diverse genetic structure. Considering various genetic discoveries taking place today, it is evident that deletions in the AZFc region are the most common cause of severe spermatogenic failure (SSF) in various populations studied. However, it is significant to note that there is a paucity of scientific literature on AZFc subdeletion screening among the Dravidian population. OBJECTIVE: To investigate the prevalence and association of AZFc subdeletion patterns among Dravidian men with nonobstructive azoospermia (NOA) and oligozoospermia. METHODS: A population of 354 subjects, including 120 patients with NOA, 109 with oligozoospermia, and 125 normal male controls, were screened using locus-specific sequence tag site markers. RESULTS: We found 21 (9.17%) patients with classical AZF deletion, while no deletions were observed in controls. After excluding the samples with AZF deletions, the remaining 208 infertile and 125 control samples were screened for partial AZFc deletions using a standardized multiplex polymerase chain reaction and on analysis revealed that 13 (6.25%) of the infertile samples possessed gr/gr subdeletions and 15 (7.21%) of the infertile samples possessed b2/b3 subdeletions. Six (4.8%) of the normal samples were found to carry gr/gr subdeletions and two (1.6%) had b2/b3 deletions. The b1/b3 deletion was not observed in any of the patient and control samples screened. CONCLUSION: Our finding shows that there is a strong association between b2/b3 subdeletion and SSF in the Dravidian population (odds ratio, 4.78; 95% confidence interval 1.07-21.26) (p=0.018). Further studies, including gene copy typing for DAZ and CDY genes and a comprehensive haplogrouping analysis, are recommended in a large and well-selected patient group to elude the genetic mechanism behind this association.

45,X karyotype in an infertile man: how is this possible?

The case was male, 32 years old, with a nonobstructive azoospermia diagnosis and an initial 45,X karyotype. We evaluated by classical cytogenetic methods, C and NOR banding, fluorescent in situ hybridization, and polymerase chain reaction investigations. After investigation, we found the following karyotype: 45,X,dic(Y;22)(q11.223;p11.2). This investigation contributes to our understanding of how chromosome rearrangements can influence fertility processes and how important it is to perform a cytogenetic analysis in infertility cases.

DAZ duplications confer the predisposition of Y chromosome haplogroup K* to non-obstructive azoospermia in Han Chinese populations.

STUDY QUESTION: What are the genetic causes for the predisposition of certain Y chromosome haplogroups (Y-hgs) to spermatogenic impairment? SUMMARY ANSWER: The AZFc(azoospermia factor c)/DAZ (deleted in azoospermia) duplications might underlie the susceptibility of Y-hg K* to spermatogenic impairment. WHAT IS KNOWN ALREADY: The roles of Y chromosomal genetic background in spermatogenesis are controversial and vary among human populations. Individuals in predisposed Y-hgs may carry some genetic factors, which might be a potential genetic modifier for the Y-hg-specific susceptibility to spermatogenic impairment. STUDY DESIGN, SIZE, DURATION: A total of 2444 individuals with azoospermia or oligozoospermia and 2456 healthy controls were recruited to this study from March 2004 and January 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a two-stage association study to investigate the risk and/or protective Y-hgs for spermatogenic impairment. In addition, the genetic causes for the predisposition of certain Y-hg to spermatogenic impairment were investigated. Deletion typing and DAZ gene copy number quantification were performed for individuals in predisposed Y-hgs. MAIN RESULTS AND THE ROLE OF CHANCE: Y-hgs K* and O3e* showed significantly different distribution between cases and controls consistently in two-stage studies. Combined analyses identified significant predisposition to non-obstructive azoospermia in Y-hg K* [odds ratio (OR) 8.58; 95% confidence interval (CI) 3.31-22.28; P = 1.40 × 10⁻5], but a protecting effect in Y-hg O3e* (OR 0.64; 95% CI 0.53-0.78; P = 4.20 × 10⁻5). Based on the dynamic nature of the Y chromosome, we hypothesized that Y-hgs K* and O3e* may be accompanied by modifying genetic factors for their predisposing or protecting effects in spermatogenesis. Accordingly, we quantified the multi-copy DAZ gene, which has variable copy numbers between individuals and plays an important role in spermatogenesis. In combined analysis, we found that the over-dosage of DAZ was significantly more frequent in Y-hg K* than in O3e* (OR 4.79; 95% CI 1.67-13.70; P = 6 × 10⁻³). LIMITATIONS, REASONS FOR CAUTION: Owing to the inconsistency of genetic background, it remains to be determined whether the results derived from Han Chinese populations are applicable to other ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study can advance the etiology of spermatogenic impairment, and also shed new light on Y chromosome evolution in human populations. Y-hg-specific genetic factors of modifying spermatogenic phenotypes deserve further investigation in larger and diverse populations.

Y chromosome-linked B and NK cell deficiency in mice.

There are no primary immunodeficiency diseases linked to the Y chromosome, because the Y chromosome does not contain any vital genes. We have established a novel mouse strain in which all males lack B and NK cells and have Peyer's patch defects. By 10 wk of age, 100% of the males had evident immunodeficiencies. Mating these immunodeficient males with wild-type females on two different genetic backgrounds for several generations demonstrated that the immunodeficiency is linked to the Y chromosome and is inherited in a Mendelian fashion. Although multicolor fluorescence in situ hybridization analysis showed that the Y chromosome in the mutant male mice was one third shorter than that in wild-type males, exome sequencing did not identify any significant gene mutations. The precise molecular mechanisms are still unknown. Bone marrow chimeric analyses demonstrated that an intrinsic abnormality in bone marrow hematopoietic cells causes the B and NK cell defects. Interestingly, fetal liver cells transplanted from the mutant male mice reconstituted B and NK cells in lymphocyte-deficient Il2rg(-/-) recipient mice, whereas adult bone marrow transplants did not. Transducing the EBF gene, a master transcription factor for B cell development, into mutant hematopoietic progenitor cells rescued B cell but not NK cell development both in vitro and in vivo. These Y chromosome-linked immunodeficient mice, which have preferential B and NK cell defects, may be a useful model of lymphocyte development.

First study of microdeletions in the Y chromosome of Algerian infertile men with idiopathic oligo- or azoospermia.

The human Y chromosome is essential for human sex determination and spermatogenesis. The long arm contains the azoospermia factor (AZF) region. Microdeletions in this region are responsible for male infertility. The objective of this study was to determine the frequency of Y microdeletions in Algerian infertile males with azoospermia and oligoasthenoteratozoospermia syndrome (OATS) and to compare the prevalence of these abnormalities with other countries and regions worldwide. A sample of 80 Algerian infertile males with a low sperm count (1-20 × 10(6) sperms/ml) as well as 20 fertile male controls was screened for Y chromosome microdeletions. 49 men were azoospermic and 31 men had OATS. Genomic DNA was isolated from blood and polymerase chain reaction was carried out with a set of 6 AZFa, AZFb and AZFc STS markers to detect the microdeletions as recommended by the European Academy of Andrology. Among the 80 infertile men screened for microdeletion, 1 subject was found to have microdeletions in the AZFc (sY254 and sY255) region. The deletion was found in azoospermic subjects (1/49, 2%). The overall AZF deletion frequency was low (1/80, 1.3%). AZF microdeletions were observed neither in the OATS group nor in the control group. The frequency of AZF microdeletions in infertile men from Algeria was comparable to those reported in the literature. We suggest analyzing 6 STS in the first step to detect Y microdeletions in our population.

A fresh look at the male-specific region of the human Y chromosome.

The Chromosome-centric Human Proteome Project (C-HPP) aims to systematically map the entire human proteome with the intent to enhance our understanding of human biology at the cellular level. This project attempts simultaneously to establish a sound basis for the development of diagnostic, prognostic, therapeutic, and preventive medical applications. In Iran, current efforts focus on mapping the proteome of the human Y chromosome. The male-specific region of the Y chromosome (MSY) is unique in many aspects and comprises 95% of the chromosome's length. The MSY continually retains its haploid state and is full of repeated sequences. It is responsible for important biological roles such as sex determination and male fertility. Here, we present the most recent update of MSY protein-encoding genes and their association with various traits and diseases including sex determination and reversal, spermatogenesis and male infertility, cancers such as prostate cancers, sex-specific effects on the brain and behavior, and graft-versus-host disease. We also present information available from RNA sequencing, protein-protein interaction, post-translational modification of MSY protein-coding genes and their implications in biological systems. An overview of Human Y chromosome Proteome Project is presented and a systematic approach is suggested to ensure that at least one of each predicted protein-coding gene's major representative proteins will be characterized in the context of its major anatomical sites of expression, its abundance, and its functional relevance in a biological and/or medical context. There are many technical and biological issues that will need to be overcome in order to accomplish the full scale mapping.

The audiological characteristics of a hereditary Y-linked hearing loss in a Chinese ethnic Tujia pedigree.

OBJECTIVE: To investigate audiometric characteristics of hearing loss in a large Chinese ethnic Tujia family and determine its hereditary type. METHODS: Total 76 live individuals were investigated in the notable 84 members of this family. The detailed audiometric evaluations were undertaken for the proband and his 47 family members. The degrees of sensorineural hearing impairment were defined as an air/bone gap <15dB hearing loss averaged over 0.5, 1 and 2kHz. The severity of hearing loss was established based on the hearing ability of the better ear, averaged over 0.5, 1, 2 and 4kHz, and classified into four categories: mild, moderate, severe and profound. RESULTS: Nineteen patrilineal relatives of the 76 live members had hearing impairment. The age of onset ranged from 7 to 21 years old with the average of 13.2 years. The audiometric defect was described by auditory curves of a high frequency in 47% of the patients. Affected members in this family demonstrated a non-syndromic, late onset, bilateral, symmetrical, postlingual and sensorineural hearing loss. CONCLUSIONS: The audiometric configuration in males of the pedigree is consistent with the hereditary Y-linked hearing loss. Thus we speculate that a putative gene on the Y chromosome could contribute to the cause of the disease.

The large Chinese family with Y-linked hearing loss revisited: clinical investigation.

CONCLUSION: The DFNY1 phenotypes shared many characteristics with some autosomal dominant hearing loss, in the aspects of age of onset, severity and audiometric configuration. However, the typical, outstanding feature of this trait was its remarkable pattern of inheritance. Similar traits, if ever encountered, can be most easily identified by discerning this exceptional and rare pattern of inheritance. OBJECTIVES: To analyze the audiological features in Chinese Y-linked non-syndromic hearing impairment, the extended DFNY1 family. SUBJECTS AND METHODS: A nine-generation Chinese family (DFNY1) was ascertained and expanded from the year of 2000 to 2006. The audiometric evaluations included pure-tone audiometry, tympanometry, and auditory brainstem responses. Some subjects received computerized tomography scan of the temporal bone. RESULTS: 52 out of 276 members in this family received clinical examinations. 24 live subjects had hearing impairment consisting of 23 patrilineal males and one female. In the affected lineage, 92% patrilineal males were well characterized as having hearing loss and 2 children remained to be diagnosed. Based on the audiological examinations on the male members, the degree of hearing loss was from mild (3 patients), moderate (7 patients) to severe (11 patients). The audiometry displayed 48% subjects with sloping in high frequencies, 38% flat in all frequencies, and the rest (14%) the U-shape. The age of onset ranged from 5-27 years with the average of 11.5 years.

Characterization of a de novo unbalanced Y;autosome translocation in a 45,X mentally retarded male and literature review.

OBJECTIVE: To describe the molecular and cytogenetic characterization of a de novo unbalanced Y;autosome translocation in a 45,X mentally retarded male. DESIGN: Descriptive case study and literature review. SETTING: Tertiary medical center. PATIENT(S): A 17-year-old 45,X mentally retarded male with no stigmata of Turner syndrome. INTERVENTION(S): Molecular and cytogenetic investigations, physical examination, and hormonal assays. MAIN OUTCOME MEASURE(S): Cytogenetic analysis, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (CGH), and polymorphic DNA marker analysis. RESULT(S): The FISH showed a Y/18p translocation. Array CGH revealed a loss of distal chromosome 18p material and a loss of part of Yq material corresponding to deletions of chromosomal segments of 18pter-->18p11.2 and Yq11.221-->Yqter. Polymorphic DNA markers analysis showed that the X chromosome was of maternal origin and the deletion of 18p was of paternal origin. CONCLUSION(S): This study confirms the usefulness of array CGH in the detection of subtle chromosomal rearrangements resulting in an unbalanced Y;autosome translocation.

Clinical implications of the detection of Y-chromosome mosaicism in Turner's syndrome: report of 3 cases.

OBJECTIVE: To determine the clinical implications of the presence of a Y chromosome in Turner's syndrome patients with karyotype abnormalities. DESIGN: To investigate the presence of Y-chromosome sequences in different tissue samples. SETTING: Endocrinology outpatient clinic of a federal university in Brazil. PATIENT(S): Five Turner's syndrome patients with karyotype abnormalities such as marker chromosomes, additional material, or ring chromosomes. INTERVENTION(S): Peripheral blood, oral epithelial cells, and hair root samples were collected. MAIN OUTCOME MEASURE(S): The SRY gene and the DYZ3 repeat region were amplified by polymerase chain reaction followed by gel electrophoresis mobility of amplified genomic DNA, and ultraviolet visualization. Prophylactic gonadectomy was offered to the Y-positive patients. RESULT(S): The analysis of the different tissues revealed that three of the five patients studied presented Y-chromosome mosaicism. These three patients underwent prophylactic gonadectomy, and in one of them, the histopathologic study of the gonads disclosed hilus cell hyperplasia and stromal luteoma with contralateral nodular hyperthecosis. CONCLUSION(S): A systematic search for Y-chromosome mosaicism in Turner's syndrome patients is justified by the risk of developing gonadal tumors or androgen-producing lesions.

Discrepancies in the laws on identifying foetal sex and terminating a pregnancy in India.

Laws that regulate the identification of a foetus and the termination of a pregnancy in India are shaped by their social context. The Medical Termination of Pregnancy Act, 1971, discriminates against unmarried women by not recognising that unwanted pregnancies in unmarried women could result in at least as much anguish and suffering as that experienced by married women. While the MTP Act permits the abortion of foetuses with disabilities, the Pre-conception and Pre-natal Diagnostic Techniques (Prohibition of Sex Selection) Act's ban on identifying the foetus's sex prevents the use of sex-detection to identify foetuses at high risk of sex-linked diseases.

Surnames as markers of pathologies--two statistical techniques and their applications.

The objective of this research is to propose and to validate two different statistical techniques to test the hypothesis of an association between surnames and pathologies, in a population participating in a screening procedure for a given pathology. We propose two statistical methods: a first technique is based on the rarefaction method, and second one is based on the principle of resampling, and it can be considered a special case of a randomisation test. Both the techniques are applied to a data set of babies screened for congenital hypothyroidism (CH), and they gave similar results. The large overlapping of the results seems to suggest a substantial validity of the proposed techniques.

[Detection of POU3F4 gene mutations in the Chinese pedigree with Y-linked hereditary hearing impairment].

OBJECTIVE: To analyze the mutations of candidate POU3F4 gene in the Chinese pedigree with Y linked hereditary hearing impairment. METHODS: Polymerase chain reaction (PCR) reactions were performed with five pairs of primer in the coding sequence of POU3F4 gene. PCR-single-strand conformation polymorphism (PCR-SSCP) was subsequently applied in the 43 individuals of DFNY1 family for screening the gene mutations. RESULTS: The PCR amplification fragments showed well quality in the five pairs of primer and further analysis with PCR-SSCP showed no any polymorphism and mutations in the members. CONCLUSIONS: The possibility of the deafness gene POU3F4, which locates on the translocation region on X and Y chromosome, contributed to the Y linked family deafness was successfully ruled out. It may imply that the causal gene of the DFNY1 family locate on the Y chromosome.