Hum. Reprod. Advance Access published online on March 7, 2008
Human Reproduction, doi:10.1093/humrep/den069
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Do we need to search for gr/gr deletions in infertile men in a clinical setting?
1 Research Centre for Reproduction and Genetics, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium 2 Centre for Medical Genetics, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium 3 Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium 4 Centre for Outcomes Research and Laboratory for Experimental Surgery, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
5 Correspondence address. Tel: +32-2-477-64-69; Fax: +32-2-477-68-60; E-mail: katrien.stouffs{at}uzbrussel.be
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Abstract |
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BACKGROUND: Partial deletions of the AZFc region of the Y chromosome such as gr/gr deletions have been detected in infertile patients as well as in control groups. The impact of these gr/gr deletions on the etiology of male infertility remains unknown. In the present study, we investigated the presence of gr/gr deletions in Caucasian men.
METHODS: gr/gr deletions were analyzed by using markers sY1291, sY1191 and sY1197 and by investigating the presence of single nucleotide variants (SNV) in DAZ and CDY1 genes in patients with azoospermia (n = 44), cryptozoospermia (n = 51) or severe oligozoospermia (n = 92). Control groups consisted of men with normal spermatogenesis on testicular biopsy (n = 33), normozoospermia (n = 278) or proven fertility (n = 83).
RESULTS: We observed 20 gr/gr deletions, with eight in infertile patients (4.3%) and 12 in the control groups (3.0%), which was not significantly different. DAZ SNV analysis revealed eight different deletion patterns in patients and controls.
CONCLUSIONS: In the present study, no significant differences in the frequency of gr/gr deletions between different patient and control groups were observed. We concluded that the relationship between gr/gr deletions and male infertility remains unclear and that it is too early to systematically test for gr/gr deletions for infertile couples seeking assisted reproduction treatment.
Key words: gr/gr deletions/male infertility/microdeletion/Y chromosome
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Introduction |
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Infertility is affecting
10–15% of couples with a desire to have children. In about half of these couples, a male factor can be assigned as the underlying cause. Despite efforts during the last decennia to clarify the exact nature of male infertility, a large number of men are diagnosed as having an ‘idiopathic male infertility’. Many studies reported on the presence of mutations or polymorphisms involved in male infertility (reviewed in Ferlin et al., 2006
; Krausz, 2007; Tüttelmann et al., 2007). Yet, these mutations can only explain the origin of the fertility problems of a very limited number of patients. Moreover, some of these data could not be confirmed in further studies, such as the presence of mutations in the SYCP3 gene (Miyamoto et al., 2003; Stouffs et al., 2005a; Krausz, 2007; Martinez et al., 2007). Sample size and ethnic or geographic differences can explain part of the observed discrepancies. Therefore, in most routine genetic laboratories, tests are limited to the examination of karyotype abnormalities and the presence of Yq microdeletions in men with idiopathic infertility of a non-obstructive nature.
The involvement of the Y chromosome in male infertility is obvious. By performing a systematic analysis of over 80 publications describing the prevalence of Yq microdeletions, we found an overall prevalence of 7.6%. These Yq microdeletions are more often found in patients with non-obstructive azoospermia (10%) compared with patients with severe oligozoospermia (6%). About 65% of the deletions originate from the removal of the complete AZFc region. This region is characterized by the presence of a large number of amplicons, which are large repeat sequences (Skaletsky et al., 2003). Deletions of the whole AZFc region are caused by recombination between amplicons b2 and b4 (Fig. 1A) (Kuroda-Kawaguchi et al. 2001). Recombination between repeats is also a major mechanism behind the origin of deletions of the other AZF regions, i.e. AZFa and AZFb. Gaining more insight into the structure of the Y chromosome also shed new light on other possible deletions on the Y chromosome (Repping et al., 2003). Besides the b2/b4 deletion, removing the whole AZFc region, partial deletions of the AZFc region have been reported. Four such partial deletions are called the gr/gr, b1/b3, b2/b3 and b3/b4 deletions (Repping et al., 2003; Ferlin et al., 2005). The gr/gr deletions are a common nominator for deletions caused by recombination between amplicons g1/g2, r1/r3 and r2/r4. This 1.6 Mb deletion removes two copies of the DAZ gene, one copy of CDY1 and one copy of the BPY2 gene. The b1/b3 and b2/b3 deletions are usually found in about equal frequencies in patient and control samples (Repping et al., 2004b; Hucklenbroich et al., 2005; Lynch et al., 2005), except in the study of Wu et al. (2007), in which more b2/b3 deletions were detected in the patient group compared with control men. Unfortunately, the number of reports on these partial AZFc deletions is too small to draw robust conclusions. Although several papers have reported on the presence of gr/gr deletions, its relationship with male infertility remains unclear. In this paper, we report our data on the frequency of gr/gr deletions in infertile men and investigated the influence of the use of different control groups. Since men with a gr/gr deletion are missing two DAZ genes and one CDY1 gene, we have analyzed all patients with a gr/gr deletion for the presence of the DAZ and CDY1 gene by single nucleotide variants (SNV) analysis.
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Materials and Methods |
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Infertile patients and controls
Blood samples from 187 patients with fertility problems were analyzed for the presence of gr/gr deletions. Patients included in our study were of Caucasian origin living in Belgium or the Netherlands. Patients were diagnosed with non-obstructive azoospermia (no spermatozoa in at least two ejaculates after centrifugation) (n = 44), cryptozoospermia (sperm concentration <0.1 x 106/ml) (n = 51) or severe oligozoospermia (sperm concentration 0.1–5 x 106/ml) (n = 92).
For all azoospermic patients, testicular sperm extraction (TESE) was performed, during which a testicular biopsy was also taken for histological examination within the frame of their fertility treatment (Tournaye et al., 1997). Histological examination of testicular tissues was performed in the pathology department of our university hospital. The final description of the testicular phenotype reported in this study is based on the most advanced stage of spermatogenesis observed in the histological sample, combined with the absence or presence of spermatozoa in testicular tissue or in the ejaculate. When a heterogeneous testicular phenotype was observed, patients were categorized according to the most advanced stage of spermatogenesis found in testicular tissues. When, for example, the histology showed tubuli with Sertoli cell-only syndrome (SCOS) as well as with maturation arrest, the histology of this sample was designated as maturation arrest. Moreover, if sperm was found at TESE and the histology was SCOS, these samples were referred to as incomplete SCOS.
On the basis of these criteria, 29 azoospermic patients were diagnosed with SCOS and 15 patients with a maturation arrest of spermatogenesis. All but one of the patients with maturation arrest of spermatogenesis had an arrest at the level of spermatocytes, whereas the last patient had an arrest at the level of spermatogonia.
Patients with an abnormal karyotype, b2/b4 deletions (i.e. classic AZFc deletions) or other AZF deletions, detected as previously reported (Stouffs et al., 2005b), were excluded.
A total of 394 control men from Caucasian origin and from Belgium or the Netherlands were divided into three groups: males with normal spermatogenesis on testicular biopsies (n = 33), normozoospermia (n = 278) or proven fertility (n = 83). The control group of men with normal spermatogenesis on their testicular biopsy sample were men who came to the Universitair Ziekenhuis Brussel with a post-infectious obstruction of the genital tract (n = 14) or for a vasectomy reversal (n = 19). Patients with congenital bilateral absence of the vas deferens were excluded from this control group.
Deletion detection
In a first step, the presence of partial AZFc gr/gr deletions was determined by PCR amplification of sequence tagged site (STS) sY1291 on genomic DNA (Fig. 1). In order to make a distinction between gr/gr deletions and b1/b3 deletions, markers sY1191 and sY1197 were then investigated for all men lacking sY1291 (Fig. 1 and scheme published by Giachini et al., 2005). In case of absence of a PCR fragment, amplification was repeated.
DAZ and CDY1 analysis
To further fine tune the deletions, the presence of CDY1a and CDY1b was tested for which the sequence family variant situated 7750 bp 5' of the CDY1 translation start codon was used (CDY1-7750, primerpair o1025/o1026; see Machev et al., 2004). The PCR amplification is followed by a restriction reaction with PvuII that only cuts the CDY1b copy.
A distinction between DAZ1/DAZ2 and DAZ3/DAZ4 was made by PCR amplification with STS sY587 (DAZ SNV-V) and a restriction reaction with DraI, which only cuts DAZ1/DAZ2 (DAZ1 and DAZ2 have T at position 146 of the PCR fragment, whereas DAZ3 and DAZ4 have C at this position). However, due to co-amplification of DAZL which has a C at this position, the absence of DAZ3/DAZ4 could not be verified. Comparison of the sequences also showed that DAZ and DAZL are likely to co-amplify. To further investigate the presence of these DAZ copies, we amplified and sequenced STSs DAZ SNV-I, DAZ SNV-II, DAZ SNV-III (=sY586) and DAZ SNV-IV (Table I). DAZ SNV-VI was amplified after which a restriction reaction was performed with AflIII (Table I). All SNVs are described in Fernandes et al. (2004) and Lardone et al. (2007).
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Statistical analysis
For comparison of the groups, statistical tests were applied two-tailed at the 5% level of significance. Categorical variables were analyzed by chi-square or Fisher's exact test. Continuous variables were analyzed by the t-test for independent samples. We also calculated the power associated with the available sample size.
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Results |
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Deletion detection
In a first step, sY1291 was used to detect partial deletions of the AZFc region. Twenty-one deletions of sY1291 were detected, of which nine were found among infertility patients (4.8%) and 12 among control samples (3.0%). The single man with normal spermatogenesis who has a deletion of sY1291 visited our hospital for a vasectomy reversal. Although the presence of AZF deletions is very unlikely in controls, we have tested and confirmed the absence of AZF deletions in all control samples in which marker sY1291 is absent.
Since this marker is also absent in patients with a b1/b3 deletion, we tested the presence of markers sY1191 and sY1197. The absence of sY1291, together with the presence of sY1191 and sY1197, discriminates gr/gr deletions from b1/b3 deletions and b2/b3 deletions (Fig. 1). Apparently, one patient with extreme oligoasthenoteratozoospermia (OAT) had a b1/b3 deletion (extreme OAT6, Table II).
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Overall, after analyzing markers sY1291, sY1191 and sY1197, we identified eight infertile patients and 12 control men with a gr/gr deletion (Table III). The frequency of gr/gr deletions was not different between patient samples (4.3%) and control samples (3.0%). Even if the patient group was subdivided into azoospermic and oligozoospermic (<5 x 106 spermatozoa/ml), no statistically different frequencies were observed. Likewise, when comparing only normozoospermic men with men with extreme OAT, no significantly different results were obtained.
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The results of the current study indicate that there were no statistically significant differences of the prevalence of gr/gr deletions among the groups. A major limitation of our study relates to its small sample size. Since statistical significance was not reached, power analyses were performed. A power analysis indicates that group sample sizes of 187 (case group) and 394 (control group) achieve only 13% power to detect an absolute difference of 1.3% between the group prevalence of 4.3% and 3.0% at a significance level (alpha) of 0.05 using a two-sided chi-square test with continuity correction. Another power analysis shows that a sample size of 2637 in the case group and 5556 in the control group (8193 participants in total) would be needed to detect a difference of 1.3% in gr/gr prevalence for an alpha level of 0.05 and 80% power.
The concentration of spermatozoa was compared between normozoospermic control samples with or without a gr/gr deletion (Table IV). The average sperm concentration of men with and those without gr/gr deletion was 69.9 and 91.3 million spermatozoa/ml, respectively. Similarly, when analyzing the total sperm numbers, the percentage of fast forward moving sperm cells and the morphology, no differences were observed (Table IV).
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DAZ and CDY1 analysis
The presence of specific DAZ and CDY1 gene copies was investigated in patients with a gr/gr deletion. We found that CDY1a was absent in six patients and seven controls. Surprisingly, we detected two controls (normozoospermia 3 and normozoospermia 4) for whom both copies of CDY1 were present (Table II).
When using marker sY587 (DAZ SNV_V), we detected 13 men who were apparently missing DAZ1/DAZ2 (Table V). However, since the absence of DAZ3/DAZ4 could not be confirmed, we also analyzed other DAZ SNVs. The data are presented in Table V. Eight different deletion patterns were observed. Patterns 2 and 4 correspond to the expected pattern when, respectively, DAZ1/DAZ2 or DAZ3/DAZ4 are deleted. However, also other deletion patterns were observed.
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According to the SNV analysis, patient SCOS1 probably has a deletion of DAZ2 and DAZ4. The presence of DAZ3 could not be confirmed. However, since for SNV_II both an A and a G are observed, DAZ3 is probably amplified. Deletion pattern 3 most probably resembles deletion of DAZ3/DAZ4, but SNV_III and SNV_IV give conflicting results on the presence of DAZ2. Similarly, pattern 5 presumably represents the deletion of DAZ1/DAZ2, but SNV_I and SNV_VI are inconsistent for DAZ4. Two controls have deletion pattern 6, for which SNV_II, SNV_III and SNV_IV predict the absence of DAZ1 and DAZ2. SNV_I would suggest that only DAZ4 is present, whereas according to SNV_VI, DAZ4 is deleted. Presuming that DAZ1 and DAZ2 are indeed absent, only DAZ3 was amplified for this SNV. Only one man with proven fertility was found with deletion pattern 7: DAZ1/DAZ2 are missing according to SNV_II, SNV_III and SNV_IV. According to SNV_I and SNV_VI, DAZ4 is present. However, as indicated by SNV_VI, also DAZ1 or DAZ2 or DAZ3 must be present. Presumably, DAZ3 is present. Yet, the presence of DAZ3 could not be confirmed. For normozoospermia 4, all DAZ genes appeared to be present (pattern 8).
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Discussion |
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During the last 3 years, several reports have been published in which the presence of gr/gr deletions was investigated. Although nearly 10 000 patients and controls have been analyzed, the pathogenic role of the gr/gr deletion remains unclear. As a consequence, it remains ambiguous whether gr/gr deletions should be analyzed in a clinical setting. Possible explanations for the discrepancy between the published studies might be due to differences in sampling between the examined patient and control groups or to ethnic differences between the different studies. Therefore, we have set up a study with clearly defined patient and control groups to gain more insight into the frequency of gr/gr deletions in Caucasian men living in Belgium or The Netherlands. No statistically significant differences were observed between our patient and control groups analyzed.
In literature, statistically significant differences between patients and controls were found in some of the reports (Repping et al., 2003; Machev et al., 2004; de Llanos et al., 2005; Ferlin et al., 2005; Giachini et al., 2005, 2007; Lynch et al., 2005), whereas other studies could not confirm the relationship between gr/gr deletions and male infertility (Hucklenbroich et al., 2005; Carvalho et al., 2006; de Carvalho et al., 2006; Fernando et al., 2006; Ravel et al., 2006; Zhang et al., 2006; Imken et al., 2007; Lardone et al., 2007; Lin et al., 2007; Wu et al., 2007; Zhang et al., 2007). Tüttelmann et al. (2007) recently reviewed the literature and concluded that the overall prevalence of gr/gr deletions is significantly increased in infertile men.
Another discrepancy between different published studies was the method used to investigate the presence of gr/gr deletions and consequently also the interpretation of the results. In most studies, STS analysis was performed to search for partial AZFc deletions. Generally, the absence of sY1291, together with the presence of sY1191 and sY1197, was believed to be diagnostic for gr/gr deletions. Also other or extra markers have been used to discover or fine tune partial AZFc deletions. Not all reports document the investigation of DAZ and CDY1 copies. Theoretically, in the case of a gr/gr deletion, always one copy of CDY1 and two copies of the DAZ gene family should be missing. However, we and others found men who are lacking sY1291, but are apparently retaining all copies of CDY1 (normozoospermia 3 and normozoospermia 4). Machev et al. (2004) reported a control who had DAZ1/DAZ2 missing, but with all copies of CDY1 present. They suggested that this might be a b1/b3 deletion. However, a b1/b3 deletion could be excluded since markers sY1191 and sY1197 were present in the man from our control group (Fig. 1 and Table II). Yet, when looking at the results of the DAZ SNV analysis of normozoospermia 4, also all DAZ gene copies appear to be present. For this man from our control group, possibly a deletion followed by a duplication has occurred, as suggested by Lin et al. (2007). However, this would predict the presence of four DAZ genes, but with the duplication of one DAZ gene pair and deletion of the other pair. Yet, for our patient, four different DAZ copies are apparently present. Further research, such as quantitative analysis of the DAZ genes, will have to elucidate the type of deletion present in this man. Alternatively, the region in which sY1291 is located might be polymorphic for this man, reducing the amplification efficiency of this marker.
When comparing the results of all DAZ SNVs analyzed, conflicting results were obtained. For 11 men, the data obtained by the restriction reaction with sY587 could not be confirmed. However, in literature, conclusions were mostly based on the analysis of this marker alone. The alteration of the SNV patterns might be caused by homologous recombination between amplicons of the AZFc region or, as also suggested by Lepretre et al. (2005), gene conversion events might underlie these observations (Repping et al., 2004a). Clearly, more research is necessary to investigate which gene copies are missing and whether analysis with sY587 alone is reliable.
It has been suggested that the presence or absence of specific gene copies is associated with male infertility. In the studies of Giachini et al. (2005) and Ferlin et al. (2005), a correlation between the absence of CDY1a and male infertility was suggested. In the present study, the absence of CDY1a was found in patients as well as in controls, in about equal frequencies (Table II). Also the absence of the DAZ1/DAZ2 gene pair was found in patients as well as in controls. From these data, we can conclude that the same gene copies are absent in patients and controls. We cannot exclude that other mutations are present in other infertility-related genes.
What does this mean for clinical practice?
The literature shows that gr/gr deletions can be found in patients with different types of fertility problems and even in controls with normozoospermia (Tüttelmann et al., 2007). When comparing the sperm concentration from men with normozoospermia with and without a gr/gr deletion, we concluded that the average sperm concentration is statistically the same, although we must mention that the number of gr/gr-deleted normozoospermic men was low. Sperm concentrations of normozoospermic men with gr/gr deletions were given in the manuscripts of Hucklenbroich et al. (2005), Fernando et al. (2006), Ravel et al. (2006) and Zhang et al. (2006), but mostly no comparison with non-gr/gr-deleted controls was given. Zhang et al. (2006) also detected no differences in sperm concentration in nine gr/gr-deleted normozoospermic men versus 80 wild-type men.
Possibly, a gr/gr deletion might influence the sperm concentration when expressed with another gene or co-factor. Until today, this co-factor hypothesis remains unclear. Mutations or polymorphisms in genes homologous to DAZ or CDY1 might be co-responsible for the fertility problems. In the DAZL gene of gr/gr-deleted men, no mutations were found (Giachini et al., 2005). In this respect, our further research will focus on the CDY2 copies. Although CDY2 genes are expressed in all stages of spermatogenesis and the expression of CDY1 genes is restricted to spermatids and spermatozoa, it might be that in these cells co-expression of CDY1 and CDY2 copies are necessary (Kleiman et al., 2003). As gr/gr deletions can be found in normozoospermic men, these second factor(s) might have a greater impact on male infertility than the gr/gr deletion itself.
Overall, we are convinced that it is too early to advise to perform routine testing for the presence of gr/gr deletions in infertile men in a clinical setting. One may argue that each couple has the right to know the origin of their fertility problems. On the other hand, it is hard to explain to the couple that a potential risk factor has been found, but that probably at least one extra, yet unknown co-factor must be involved. If this second factor is Y-linked, all sons will probably also suffer from fertility problems. On the other hand, an autosomal factor would reduce the risks and in the case of X-linked factors, there is no risk for the next generation. Furthermore, when more than two genes or genetic factors are involved or when the cause of the fertility problems is multifactorial, the risks of transmitting infertility to the next generation will be limited. Thus, when confronted with gr/gr testing, couples will probably have more questions than answers.
Finally, we must also consider the costs versus the benefits of the test. Screening for the presence of Yq microdeletions in infertile men is useful, because the observation of a deletion will have a diagnostic value, especially in case of an AZFa or AZFb deletion. Further treatment such as TESE might be superfluous for these men. Furthermore, if detected, the genetic consequences for the offspring are clear cut. However, today the presence of a gr/gr deletion will be of very little additional diagnostic value and the consequences for the next generation are unclear.
In conclusion, current data show that there is not enough evidence to routinely analyze for gr/gr deletions in infertile men before assisted reproduction treatment, but that there is a need for more research on how to test for and understand gr/gr deletions.
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Funding |
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The work was supported by grants from the Fund for Scientific Research Flanders (Belgium), and from the Research Council and a Concerted Action of the Free University of Brussels (Vrije Universiteit Brussel).
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Acknowledgements |
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K.S. is a postdoctoral fellow of the Fund for Scientific Research Flanders (Belgium) (FWO-Vlaanderen). We wish to thank the laboratory, clinical and paramedical staff of the Centre for Medical Genetics, the Centre for Reproductive Medicine and the Department of Pathology of the UZ Brussel for their assistance. Special thanks to Deborah Vandermaelen for her technical help.
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References |
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Submitted on September 5, 2007; resubmitted on February 4, 2008; accepted on February 12, 2008.
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