男性不育患者Y染色体微缺失筛查方法的建立和初步应用

目的 建立一套Y染色体微缺失的多重PCR筛查方法，对无精症或少精症男性不育患者进行Y染色体微缺失的常规筛查。方法 建立5套稳定和可靠的多重PCR筛查方法，对进行单精子卵细胞浆注射治疗的87例无精症和少精症患者及进行睾丸活检的30例无精症患者做Y染色体微缺失的检测。结果 共有19例发现微缺失(16．2％)，其中61例少精症患者中发现11例(18．0％)，56例无精症患者中发现8例(14．3％)。结论 Y染色体微缺失的多重PCR筛查方法是易行和可靠的，对无精症和少精症患者有必要进行Y染色体微缺失的常规筛查。     

Y chromosome microdeletions in Tunisian infertile males

AIM: To determine frequency of Y microdeletions in azoospermic and oligospermic Tunisian infertile males. METHODS: A Sample of 146 Tunisian infertile males with a low sperm count (<5 x 10(6) sperms per mililiter) and normal karyotype was screened for Y chromosome microdeletions. 76 men were azoospermic and 70 men were oligospermic. Genomic DNA was isolated from blood and multiplex PCR was carried out with a set of 20 AZFa, AZFb and AZFc STS markers to detect the microdeletions as recommended by the European Academy of Andrology. RESULTS: In 10/146 (6.85%) subjects AZF deletions were observed. Of these ten males with microdeletions, 9/10 subjects were azoospermic (90%), 1/10 was oligospermic (10%). Frequency of microdeletions in azoospermic men was 9/76 (11.84%). None of the patients showed isolated microdeletion in the AZFa region, but one azoospermic man had deletion in the AZFb region. Eight azoospermic patients and one oligospremic man have AZFc microdeletions. AZFc and AZFb were deleted in three azoospermic patients. AZFc, AZFb and AZFa were deleted in three azoospermic patients We estimate the sensitivity of the test comprising six STS in our sample to be 90%. CONCLUSION: The incidence of Yq microdeletions in the study population of infertile Tunisian men falls within the range published in other countries. We suggest to analyze 9STS in the first step to detect efficiently Y microdeletions in our population.     

Detection of Y chromosome microdeletions in AZF region by liquid chip technology]

OBJECTIVE: To establish a liquid chip technology to detect Y chromosome microdeletions in Chinese infertile males with azoospermia or oligozoospermia. METHODS: Multiplex PCR and liquid chip technology were used to detect the Y chromosome microdeletions in AZF region in 178 infertile patients with azoospermia and 134 infertile patients with oligozoospermia as well as 40 fertile control men. RESULTS: Forty out of 312 patients (12.8%) were found to have deletions in AZF region. The microdeletion frequency was 14%(25/178) in the azoospermic group, 9.6%(11/114) in the oligospermic and 20%(4/20) in the severe oligospermic group. CONCLUSION: The authors developed a high-throughput, fast and simple assay to screen the AZF region microdeletions of Y chromosome.     

Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction

Y chromosome deletions encompassing the AZFc region have been reported in 13% of azoospermic men and 7% of severely oligozoospermic men. We examined the impact of these Y deletions on the severity of testicular defects in 51 azoospermic men undergoing intracytoplasmic sperm injection (ICSI) after testicular sperm extraction (TESE) and 30 men with severe oligozoospermia undergoing ICSI after ejaculation of spermatozoa. In addition, five azoospermic patients shown previously to have Y chromosome deletions underwent histological evaluation of their previously obtained testis biopsy specimens. A further 27 azoospermic men underwent TESE-ICSI, but not Y chromosome DNA testing. Ten of 51 azoospermic men (20%) who underwent TESE-ICSI and Y-DNA testing were found to be deleted for portions of the Y chromosome AZFc region. Of these 10, five had spermatozoa retrievable from the testis, and in two cases the wives became pregnant. Of the 41 azoospermic men with no Y chromosome deletion, 22 (54%) had spermatozoa retrievable from the testis, and in 12 cases (29%) the wives became pregnant. Four of 30 (13%) severely oligozoospermic patients were found to be deleted for AZFc and in three (75%) of these pregnancy was achieved. The other 26 severely oligozoospermic couples who had no AZFc deletions underwent ICSI, and 12 (46%) have an ongoing or delivered pregnancy. The embryo implantation rate was not significantly different for azoospermic (22%), oligozoospermic (16%), Y-deleted (14%) or Y-intact (18%) men. Of the total of 19 infertile men who had Y chromosome deletions, 14 had deletions within Y chromosome intervals 6D-6F, in the AZFc region. Twelve of those 14 had some spermatozoa (however few in number) in the ejaculate or testis. Five of the Y-deleted men had deletions that extended more proximally on the Y chromosome, and in none of these could any spermatozoa be observed in either ejaculate or testis. These results support the concept that, in azoospermic or oligozoospermic men with Y chromosome deletions limited to intervals 6D-6F (AZFc), there are generally very small numbers of testicular or ejaculated spermatozoa. Larger Y deletions, including and extending beyond the AZFc region and encompassing more Y genes, tend to be associated with a total absence of testicular spermatozoa. In those cases where spermatozoa were retrieved, the presence of Y deletions had no obvious impact on fertilization or pregnancy rate.      

Microdeletions of the Y chromosome and intracytoplasmic sperm injection: from gene to clinic

Intracytoplasmic sperm injection (ICSI) is a successful treatment option for severe male infertility, although the aetiology of the disorder remains unclear in most cases. Recently, microdeletions in the AZF region of the Y chromosome have been detected in men with azoospermia or severe oligozoospermia. In this study we investigated the prevalence of microdeletions in the AZF region of the Y chromosome in a population of men undergoing ICSI, and looked for clinical characteristics of men with and without this deletion. Blood was drawn from 164 men, who were on the waiting list for ICSI treatment: 19 were azoospermic, 111 oligozoospermic and 34 normozoospermic (after previous total fertilization failure). A total of 100 men with proven fertility served as a control. Microdeletions in the AZFc region were present in seven of the 111 oligozoospermic men (6.3%). Compared with oligozoospermic men without microdeletions, men with microdeletions had a lower concentration of follicle stimulating hormone (FSH), a lower number of motile spermatozoa and a lower frequency of abnormal findings at andrological history or examination. No microdeletions were found in the azoospermic, normozoospermic and control groups. In conclusion, microdeletions in the AZFc region are relatively frequently found in men with severe unexplained oligozoospermia. In the ICSI era this finding has an important impact because this form of male infertility is now potentially hereditary. Therefore we recommend DNA screening (and genetic counselling) before ICSI, especially in men with normal FSH, severe oligozoospermia and no abnormal clinical andrological findings.      

特发性无精子症和严重少精子症患者DAZ基因缺失的分析

目的　评估特发性无精子症和严重少精子症患者Y染色体上DAZ基因缺失的发生情况。方法　采用聚合酶链反应技术 (PCR)扩增 33例特发性无精子症和严重少精子症患者DAZ基因中的 4个序列标记位点SY15 4、SY2 5 4、SY2 5 5和SY15 5。 5 0例生育男性为阳性对照组 ,5例女性为阴性对照组。结果　 33例特发性无精子症和严重少精子症患者DAZ基因缺失率为 15 2 % ,其中 2 6例特发性无精子症患者有 4例缺失 (15 4 % ) ,1例染色体核型为 4 7,XXY ;7例特发性严重少精子症患者中有 1例缺失 (14 3% )。 4个序列标记位点在阳性对照组中均有条带扩增 ,在阴性对照组中未见条带扩增。结论　特发性无精子症和严重少精子症患者均存在DAZ基因缺失 ,特发性无精子症患者缺失率高于特发性严重少精子症患者 ,与国外报道相一致。聚合酶链反应扩增DAZ基因位点是筛选Y染色体缺失的有效方法。     

Genotyping of Israeli infertile men with idiopathic oligozoospermia

Microdeletions of the long arm of the Y chromosome involving the azoospermia factor (AZF) region are associated with severe oligo- or azoospermia. Abnormal androgen receptor (AR) structure or function has also been implicated in male infertility. To assess the contribution of these genetic defects to male infertility, 61 Israeli men with severe oligo- (n = 15) or azoospermia (n = 46), were screened for Y chromosome microdeletions, and the AR-(CAG)n repeat length. Fifty fertile Israeli men were similarly analyzed. PCR amplification of 20-54 simple tag sequences (STSs) located at Yq was used to determine the rate and extent of Y chromosome microdeletions. PCR with primers flanking the AR-(CAG)n region and subsequent size fractionation on gradient acrylamide gels were used to determine AR-(CAG)n length. Five azoospermic individuals (5/61-8.2% and 5/46-10.8% of azoospermic patients) displayed Y chromosome microdeletions. The mean CAG repeat number in infertile men was 18.6 +/- 3.0 compared with 16.6 + 2.7 in fertile men (n = 50), a statistically significant difference (p = 0.003). Y chromosome microdeletions contribute to male infertility in our azoospermic population, and the mean length of the AR-CAG is significantly longer in our infertile population than in fertile men.     

Prevalence of chromosomal abnormalities in 2078 infertile couples referred for assisted reproductive techniques

BACKGROUND: This study analyses the prevalence of karyotype changes and Yq11 microdeletions among couples referred for assisted reproduction techniques. METHODS: Prior to receiving either IVF or ICSI treatment, each partner of 2078 infertile couples was screened for karyotype changes by GTG-banding technique on peripheral lymphocytes. No subject presented with obvious phenotype of chromosomal rearrangement. All the oligo/azoospermic men with normal karyotype were further investigated by PCR for Yq11 microdeletions. RESULTS: Eighty-two out of 2078 couples (3.95%) had one partner carrying a chromosomal change, and 10 out of 202 (4.95%) men showed Yq11 microdeletions. The chromosomal rearrangements were 44 (2.1%) translocations, 23 (1.1%) gonosomal mosaics, six (0.3%) 47,XXY, five (0.24%) marker chromosomes, three (0.14%) inversions and one (0.05%) duplication. Frequency of anomalies in men and women were similar: 42 and 40 cases respectively. CONCLUSIONS: Partners of infertile couples requiring IVF or ICSI treatment appear to be affected by higher frequency of chromosomal rearrangements than the general population. Categories with greater risk were represented by men with sperm cell count <20 x 10(6) sperm/ml, and women with history of pregnancy loss.     

Y chromosome microdeletions, in azoospermic or near-azoospermic subjects, are located in the AZFc (DAZ) subregion

Submicroscopic deletions of the Y chromosome and polymorphisms of the androgen receptor (AR) gene in the X chromosome have been observed in men with defective spermatogenesis. To further define the subregions/genes in the Y chromosome causing male infertility and its relationship to polymorphisms of the AR polyglutamine tract, we screened the genomic DNA of 202 subfertile males and 101 healthy fertile controls of predominantly Chinese ethnic origin. Y microdeletions were examined with 16 sequence-tagged site (STS) probes, including the RBM and DAZ genes, spanning the AZFb and AZFc subregions of Yq11, and related to the size of trinucleotide repeat encoding the AR polyglutamine tract. Y microdeletions were detected and confirmed in three out of 44 (6.8%) of azoospermic and three out of 86 (3.5%) severely oligozoospermic patients. No deletions were detected in any of the patients with sperm counts of >0.5 x 10(6)/ml, nor in any of the 101 fertile controls. All six affected patients had almost contiguous Y microdeletions spanning the entire AZFc region including the DAZ gene. The AZFb region, containing the RBM1 gene, was intact in five of the six subjects. Y deletions were not found in those with long AR polyglutamine tracts. Our study, the first in a Chinese population, suggest a cause and effect relationship between Y microdeletions in the AZFc region (possibly DAZ), and azoospermia or near-azoospermia. Y microdeletions and long AR polyglutamine tracts appear to be independent contributors to male infertility.      

Prognostic value of Y deletion analysis. The role of current methods

Y chromosome microdeletions represent the most frequent genetic alteration in azoospermic and severely oligozoospermic men, and screening for microdeletions in AZFa, b and c are routinely performed in the major andrology and infertility centres. Since patients with Y microdeletions often require intracytoplasmic sperm injection (ICSI), the question of whether the type of the microdeletion present could have prognostic value for the presence of spermatozoa in the ejaculate or in the testes [by testicular sperm extraction (TESE)] is an interesting one. The review of the literature on this topic showed that there is still no clear genotype--phenotype relationship, i.e. similar testicular alterations may be caused by different types of microdeletions, and apparently identical microdeletions may be associated with diverse tubular damage. Even in azoospermic men, the localization of the microdeletion cannot be used as a valid prognostic parameter before TESE--ICSI to identify patients with spermatozoa in their testes. The only finding with absolute negative prognostic value is the presence of complete AZFa--c deletions, which are invariably associated with an absence of spermatozoa. Microdeletions in AZFa or AZFb seem to have promising prognostic value, but more data and gene-specific deletions have to be provided to draw clear conclusions. The absence of a clear genotype--phenotype relationship, and therefore of a prognostic value of Y deletion analysis, is probably due to the current methods used for the screening of the microdeletions. In fact, to date most centres do not use gene-specific markers but instead use anonymous primers that contribute little information to the pathogenic role of the microdeletions.     

Screening for Y chromosome microdeletions in 226 Slovenian subfertile men.

BACKGROUND: The objective of this study was to estimate the frequency of Y chromosome microdeletions in the Slovenian population of infertile men and to analyse the consequences of mutation in respect to clinical severity and prognosis. METHODS: In a controlled clinical study at the university-based medical genetics service and infertility clinic, 226 infertile men undergoing ICSI were tested. The main outcome measures included polymerase chain reaction amplification of 16 genes and gene families and 42 sequence-tagged sites in the non-recombining region of the Y chromosome, semen, testicular volume and testicular histological analysis, serum FSH concentrations, fertilization and respective pregnancy rates. RESULTS: The incidence of deletions was 4.4%: 8.6% in men with azoospermia and 1.5% in men with oligoasthenoteratozoospermia. Isolated gene deletions were not identified. No statistically significant differences in clinical outcome measures were found in patients with mutations versus patients without mutations. High fertilization (49%) and pregnancy (43%) rates with sperm of patients with Y chromosome deletions were obtained. CONCLUSIONS: Testing for gene-specific microdeletions does not contribute significantly to the sensitivity of microdeletion test. Fertilization and pregnancy rates obtained using sperm of patients with Y chromosome deletions were comparable with those achieved in conventional IVF.     

FISH analysis of chromosome X,Y and 18 abnormalities in testicular sperm from azoospermic patients

BACKGROUND: Sperm extracted from testicular biopsies of azoospermic men can successfully be used for ICSI. The concern exists that testicular sperm from azoospermic men suffering from severe testicular failure may have a higher frequency of aneuploidy, which may lead to an increased risk for chromosomally abnormal offspring. METHODS: Testicular sperm from patients showing spermatogenic failure (n = 17) and from patients with normal spermatogenesis (n = 26) were analysed by fluorescence in-situ hybridization (FISH). Numerical chromosomal abnormalities for chromosomes X, Y and 18 were evaluated by FISH in a total of 1697 testicular sperm derived from 43 azoospermic patients. RESULTS: No difference was observed between the frequency of chromosomal abnormalities in testicular sperm from patients with normal spermatogenesis (5.6%) and from patients with spermatogenic failure (8.2%). However, the frequency of aneuploidy for chromosome 18 was higher in the group of azoospermic patients with spermatogenic failure than in the group with normal spermatogenesis (3.2 versus 1.3%). Within the obstructive group, sex chromosome aneuploidy (4.5%) occurred more frequently than chromosome 18 aneuploidy (1.3%; P < 0.001). Among testicular sperm derived from patients with spermatogenic failure, sex chromosomal aneuploidy (5.8%) was similar to that for chromosome 18 (3.2%). CONCLUSIONS: So far, no difference in the total frequency of chromosomal abnormalities has been observed between patients with normal spermatogenesis and patients with severe testicular failure. However, aneuploidy for chromosome 18 was higher in the group with spermatogenic failure.     

Detection of sperm in men with Y chromosome microdeletions of the AZFa,AZFb and AZFc regions

BACKGROUND: Y chromosome microdeletions are associated with severe male factor infertility. In this study, the success rate of testicular sperm retrieval was determined for men with deletions of AZF regions a, b or c. METHODS: AZF deletions were detected by PCR of 30 sequence-tagged sites within Yq emphasizing the AZFa, b and c regions. Semen analysis and diagnostic testis biopsy or testicular sperm extraction (TESE) findings were correlated with the specific AZF region deleted. RESULTS: A total of 78 men with AZF deletions included three with AZFa deletion, 11 with AZFb, 42 with AZFc, 16 with AZFb+c and six with Yq (AZFa+b+c). All men with AZFa, AZFb, AZFb+c and Yq deletions were azoospermic and no sperm were found with TESE or biopsy. Of men with isolated AZFc deletion, sperm were found in 75% (9/12) by TESE and 45% (9/20) on biopsy (56% overall); 62% (26/42) were azoospermic and 38% (16/42) severely oligozoospermic. A total of 7 patients with deletion patterns that included the complete AZFa region and 23 that included the complete AZFb region who underwent TESE or biopsy did not have sperm detected by these surgical measures. CONCLUSIONS: Microdeletion of the entire AZFa or AZFb regions of the Y chromosome portends an exceptionally poor prognosis for sperm retrieval, whereas the majority of men with AZFc deletion have sperm within the semen or testes available for use in IVF/ICSI.     

180例无精子症或严重少精子症不育男性的Y染色体微缺失检测

目的探讨不育男性无精子症或严重少精子症与Y染色体微缺失之间的关系.方法利用9个Y染色体特异序列标签位点,以多重PCR法检测无精子症或严重少精子症患者的Y染色体微缺失情况.结果 180例无精子症或严重少精子症患者中共检出Y染色体微缺失15例,缺失率为8.3%.精液正常者(对照组)20例未发现Y染色体微缺失.9例Y染色体微缺失的无精子症患者睾丸细胞学检查均未发现精子.结论 Y染色体微缺失是造成男性精子发生障碍的常见病因之一.     

Chromosome analysis of spermatozoa extracted from testes of men with non-obstructive azoospermia

Infertile men with azoospermia now have the possibility of fathering children by testicular sperm extraction combined with intracytoplasmic sperm injection. However, there are concerns about the risk of chromosomal abnormalities in their spermatozoa. We have studied aneuploidy frequencies for chromosomes 13, 21, X and Y by multicolour fluorescence in-situ hybridization (FISH) in testicular spermatozoa extracted from three men with non-obstructive azoospermia. The men were 34-37 years of age and had normal follicle-stimulating hormone (FSH) concentrations and normal 46,XY somatic karyotypes. A total of 3324 spermatozoa was analysed. The infertile patients had an elevated frequency of disomy for chromosomes 13, 21, XY disomy compared to controls but none of these reached statistical significance. Also there was no significant difference in the sex ratio or the frequency of diploidy in azoospermic patients compared to normal control donors. This first report on chromosomal aneuploidy in spermatozoa extracted from testes of patients with non-obstructive azoospermia suggests that some azoospermic men do not have a substantially increased risk of chromosomally abnormal spermatozoa.     

Lack of association between Y chromosome haplogroups and male infertility in Japanese men

The Y chromosome carries several genes involved in spermatogenesis, which are distributed in three regions in the euchromatic part of the long arm, called AZFa (azoospermia factor a), AZFb, and AZFc. Microdeletions in these regions have been seen in 10-15% of sterile males with azoospermia or severe oligozoospermia. The relatively high de novo occurrence of these microdeletion events might be due to particular chromosome arrangements associated with certain Y chromosome haplogroups. To test whether there is any association between Y chromosome types and male infertility, we studied a sample of 84 Japanese oligozoospermic or azoospermic males. The patients were analyzed for the presence of Yq microdeletions and also typed with a battery of unique event polymorphisms (UEPs) to define their Y haplogroups. Six of the infertile patients presented likely pathological microdeletions detectable with the sequence tagged sites (STS) markers used. There was no significant association between Y chromosome haplogroups and the microdeletions. We also compared the Y haplogroup frequencies in our subset sample of 51 idiopathic azoospermia patients with 57 fertile control Japanese males, and did not observe any significant differences. Contrary to previous reports, our data suggest that Y microdeletions and other molecular events causally associated with male infertility in Japan occur independently of the Y chromosome background.     

呼和浩特地区209例无精子症和严重少弱精子症患者的遗传因素调查

目的探讨染色体数目和结构异常,以及Y染色体无精子因子基因拷贝缺失与男性不育的关系。方法利用染色体G显带和PCR检测技术,对209例无精症和少弱精症患者进行外周血染色体检查,对在染色体核型分析中Y染色体部分缺失患者5例,11例小Y患者,以及1例Y染色体数目和结构均有异常的嵌合体患者,共17例进行Y染色体微缺失检测。结果共发现染色体异常核型71例,占34.9%。Y染色体微缺失患者4例。结论在无精症和少弱精症患者中存在较高频率染色体数目和结构异常,以及无精子因子基因拷贝缺失,遗传因素是造成男性不育的重要因素。     

Y chromosome microdeletions and germinal mosaicism in infertile males

Molecular deletions of the Y chromosome long arm are a frequent cause of male infertility. Because these deletions are thought to be inherited from fathers without Y chromosome deletions, the question arises as to whether their relatively high incidence in the male population could be due to the existence of a mosaicism in somatic and/or germinal paternal cells. This study included a total of 181 infertile men, among whom 18 were found to have an abnormal karyotype. In the other 163, polymerase chain reaction (PCR) analysis detected nine (5.5%) Y chromosome microdeletions. Blood, spermatozoa or testicular cells from 47 men (27 oligozoospermia, 20 azoospermia), including six Y-deleted patients, were screened for mosaicism using double target fluorescence in-situ hybridization (FISH) with Y centromeric and deleted in azoospermia (DAZ) gene-specific probes. Results indicated that: (i) percentages of double (intact Y chromosome) or single (deleted Y chromosome) fluorescent signals by FISH were in agreement with PCR data, thus demonstrating the reliability of the method; and (ii) a weak germ cell mosaicism was found in only two oligozoospermic patients, carrying 1.97 and 4.13% respectively of spermatozoa with a deleted Y chromosome. Further studies on larger populations are needed to evaluate precisely the incidence of Y deletion mosaicisms in infertile men.     

Decreased fertilization rate and embryo quality after ICSI in oligozoospermic men with microdeletions in the azoospermia factor c region of the Y chromosome

Microdeletions of the azoospermia factor (AZF) region of the Y chromosome occur in between 1 and 29% of oligozoospermic and azoospermic men, and most deletions are found in the AZFc region. These men can father children when intracytoplasmic sperm injection (ICSI) is used, but the success rate is unclear. Thus, the success rate of 19 ICSI treatments in eight couples with a microdeletion in the AZFc region of the Y chromosome was analysed retrospectively. These were compared with a control group of 239 ICSI treatments in 107 couples undergoing ICSI treatment with ejaculated spermatozoa. The fertilization rate was significantly lower in the group of Y-deleted men (55%; 95% CI: 41-69%) compared with controls (71%; 95% CI: 67-74%; P < 0.01). The embryo quality was also significantly poorer among Y-deleted men (P<0.001). Pregnancy, implantation and take-home baby rates were not significantly lower in the Y-deleted group. This study shows that ICSI in oligozoospermic men with microdeletions in the AZFc region of the Y chromosome leads to a lower fertilization rate and poorer embryo quality.     

COMMENTS

Human spermatogenesis is regulated by a network of genes located on autosomes and on sex chromosomes, but especially on the Y chromosome. Most results concerning the germ cell function of the Y genes were obtained by genomic breakpoint mapping studies of the Y chromosome of infertile patients. Although this approach has the benefit of focussing on those Y regions that contain most likely the Y genes of functional importance, its major drawback is the fact that fertile control samples were often missing. In fertile men, molecular and cytogenetic analyses of the Y chromosome has revealed highly polymorphic chromatin domains especially in the distal euchromatic part (Yq11.23) and in the heterochromatic part (Yq12) of the long arm. In sterile patients cytogenetic analyses mapped microscopically visible Y deletions and rearrangements in the same polymorphic Y regions. The presence of a Y chromosomal spermatogenesis locus was postulated to be located in Yq11.23 and designated as AZoospermia Factor (ZF). More recently, molecular deletion mapping in Yq11 has revealed a series of microdeletions that could be mapped to one of three different AZF loci: AZFa in proximal Yq11 (Yq11.21), AZFb and AZFc in two non‐overlapping Y‐regions in distal Yq11 (Yq11.23). This view was supported by the observation that AZFa and AZFb microdeletions were associated with a specific pathology in the patients' testis tissue. Only AZFc deletions were associated with a variable testicular pathology and in rare cases AZFc deletions were even found inherited from father to son. However, AZFc deletions were found with a frequency of 10–20% only in infertile men and most of them were proved to be “de novo”, i.e. the AZFc deletion was restricted to the patient's Y chromosome. Based mainly on positional cloning experiments of testis cDNA clones and on the Y chromosomal sequence now published in GenBank, a first blueprint for the putative gene content of the AZFc locus can now be given and the gene location compared to the polymorphic DNA domains. This artwork of repetitive sequence blocks called AZFc amplicons raised the question whether the AZFc chromatin is still part of the heterochromatic domain of the Y long arm well known for its polymorphic extensions or is decondensed and part of the Yq11.23 euchromatin? We discuss also the polymorphic DAZ gene family and disclose putative origins of its molecular heterogeneity in fertile and infertile men recently identified by the analyses of Single Nucleotide Variants (SNVs) in this AZFc gene locus.