Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 1646; DO: 0070187;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Yq11.221 | Spermatogenic failure, Y-linked, 2 | 415000 | Y-linked | 3 | USP9Y | 400005 |
A number sign (#) is used with this entry because this form of nonobstructive spermatogenic failure, designated Y-linked spermatogenic failure-2 (SPGFY2), is most often caused by interstitial deletions on the Y chromosome. Complete deletion of the AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. In addition, mutations in the USP9Y gene (400005) are associated with nonobstructive azoospermia and hypospermatogenesis.
About 2 to 3% of human males are infertile because of defects in sperm function, primarily due to oligozoospermia (defined as less than 10-15 million sperm per mL of semen) or azoospermia (Hull et al., 1985).
Heterogeneity of Spermatogenic Failure
For a discussion of Y-linked spermatogenic failure due to Sertoli cell-only syndrome, see 400042.
For a discussion of phenotypic and genetic heterogeneity of spermatogenic failure, see SPGF1 (258150).
Tiepolo and Zuffardi (1976) observed the involvement of Yq deletions in male infertility when they were analyzing cells from idiopathic infertile males. Molecular studies (Reijo et al., 1995; Vogt et al., 1996; Pryor et al., 1997, Foresta et al., 2001) have since shown that microdeletions at Yq11 may represent the etiologic factor in as many as 10 to 20% of cases with idiopathic azoospermia or severe oligozoospermia. Most of the deletions occur de novo and fall in 3 nonoverlapping regions, designated AZFa, AZFb, and AZFc (see Vogt et al., 1996), of which the distally located AZFc is most frequently deleted (Yen, 1998).
Foresta et al. (2001) reviewed published data on more than 4,800 infertile men who had been screened for Y-chromosome microdeletions and found that patients with Y-chromosome deletions frequently have sperm either in the ejaculate or within the testis and are therefore suitable candidates for assisted reproduction techniques. However, the authors noted that while the use of spermatozoa carrying Y-chromosome deletions may produce pregnancies, in such cases the genetic anomaly will invariably be passed on to male offspring.
A role for the human Y chromosome in spermatogenesis was first suggested by the studies of Tiepolo and Zuffardi (1976), who karyotyped 1,170 subfertile men and identified 6 azoospermic individuals with microscopically detectable deletions of distal Yq. In 4 cases in which the father was tested, all were found to carry intact Y chromosomes. On the basis of these de novo deletions in azoospermic men, Tiepolo and Zuffardi (1976) proposed the existence of a spermatogenesis gene, or 'azoospermia factor' (AZF), on Yq.
Lange et al. (2009) screened DNA samples from 2,380 patients, including 1,550 men who presented with spermatogenic failure and 830 patients in whom light microscopy revealed a structurally anomalous Y chromosome or sex reversal, and identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. Lange et al. (2009) identified idicYp and isoYp chromosomes in 18 otherwise healthy men with greatly diminished or no sperm production, and stated that such chromosomal abnormalities are among the more common genetic causes of severe spermatogenic failure.
By Southern blot analysis and in situ hybridization with Y-specific DNA probes in 3 45,X males, Andersson et al. (1988) localized AZF to interval 6 of the Y chromosome, as defined by Vergnaud et al. (1986). AZF has been divided into 3 regions, designated AZFa, AZFb, and AZFc (see Vogt et al., 1996).
By in situ hybridization with 3 different Y-specific DNA probes in a 28-year-old azoospermic male, Chandley et al. (1989) demonstrated a de novo deletion at Yq11 that resulted in loss of all distal heterochromatin.
In the screening of DNA from 21 patients with structural abnormalities in Yq, Ma et al. (1992) constructed a detailed map of interval 6. In a panel of 19 chromosomally normal azoospermic men, they screened DNA with the same set of probes and found microdeletions in 2. They suggested that these microdeletions disrupted the AZF locus.
By means of a molecular screen specific for microdeletions in interval 6 of the Y chromosome, Vogt et al. (1992) found a de novo microdeletion in 2 of 19 'chromosomally normal' sterile males. They mapped the position of the Y deletion of one patient to the distal part of Yq11.22 or the proximal part of Yq11.23, and the deletion of the other patient to the distal part of Yq11.23. These microdeletions probably did not overlap. Since AZF had been mapped to Y interval 6, Vogt et al. (1992) postulated that the microdeletion affected the functional DNA structure of the putative AZF gene.
Typing EBV-immortalized cell lines from azoospermic or severely oligospermic patients for the expression of H-Y antigen, Simpson et al. (1993) found no correlation between spermatogenic failure and the absence of HYA (JARID1D; 426000), thus separating the AZF locus region from HYA.
Ma et al. (1993) reported the isolation and characterization of a gene family located within interval 6 (subinterval XII-XIV) of Yq11.23, a region of approximately 200 kb that, when deleted, is associated with azoospermia or severe oligospermia (see RBMY1A1; 400006). Analysis of the predicted protein products suggested a possible role in RNA processing or translational control during early spermatogenesis. The expression of the genes appeared to be testis specific, and the genes showed a male-specific conservation of expression in DNA from several other mammals. The Y-chromosome RNA recognition motif (YRRM) family includes a minimum of 3 members. Ma et al. (1993) detected deletions of YRRM sequences in 2 oligospermic patients with no previously detected mutation.
Kobayashi et al. (1994) analyzed DNA from 63 Japanese men with either azoospermia or severe oligospermia whose Y chromosomes were cytogenetically normal. They examined 15 loci on the long arm between DYS7E and DYZ1, and the YRRM1 (RBMY1A1) locus. They detected microdeletions in 10 of the men; the YRRM1 gene was involved in only 3 of them. The remaining 7 patients showed deletion between DYS7C and DYS239 in common, indicating the presence of at least 1 additional gene, deletion of which causes azoospermia.
Reijo et al. (1995) studied 89 men with nonobstructive azoospermia, 78 of whom had undergone testis biopsy, revealing Sertoli cell-only syndrome (SCO; 400042) in 42 of them and testicular maturation arrest in 36. Deletions of portions of the Y chromosome long arm were found in 12 of the 89 men; all 12 deletions overlapped an approximately 5x10(5)-kb AZF region presumed to contain 1 or more genes for spermatogenesis. The 12 deletions were associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. No Y-chromosome deletions were detected in 90 fertile male controls. Using exon trapping within the deleted region, Reijo et al. (1995) identified a single-copy gene, designated DAZ (for 'deleted in azoospermia'; 400003), which is transcribed in the adult testis and appears to encode an RNA-binding protein.
Azoospermia Factor Regions
Vogt et al. (1996) analyzed 370 men with idiopathic azoospermia or severe oligozoospermia for deletions of 76 loci in Yq11 and detected different microdeletions in 13 patients. Three patients showed a microdeletion in proximal Yq11, 3 had a microdeletion in interval D13-D16, and 7 had a microdeletion in D20-D22; among patients within each group, the extension of deleted intervals was the same. Vogt et al. (1996) analyzed testis biopsies from patients with deletions in different regions of Yq11. A patient with a deletion in proximal Yq11 had SCO (only Sertoli cells but no germ cells were visible in all tubules of the testis sections). In 3 patients with a microdeletion in middle Yq11, testicular histology revealed spermatogenic arrest at the spermatocyte stage: populations of spermatogonia and spermatocytes were normal in tubules and no post-meiotic germ cells could be detected, which indicated that disruption of spermatogenesis occurred before or during meiosis at the spermatocyte stage. Results of studies in 5 patients with microdeletions in distal Yq11 suggested a post-meiotic spermatid or sperm maturation defect. Because microdeletions were found in 3 different Yq11 subregions that led to spermatogenesis disruption at different phases of the process, Vogt et al. (1996) proposed the presence of 3 spermatogenesis loci in Yq11, which they designated AZFa, AZFb, and AZFc. They proposed in addition that each locus is active during a different phase of male germ cell development.
Pryor et al. (1997) evaluated the Y chromosomes of 200 consecutive infertile men and 200 normal men and identified microdeletions in 14 infertile men (7%) and 4 normal men (2%). The size and location of the deletions varied and did not correlate with the severity of spermatogenic failure or testicular pathology: for example, of 2 patients with SCO type I, 1 had a deletion in AZFa whereas the other had an intact AZFa region but a deletion of AZFb and AZFc; and another patient with a deletion in AZFc had spermatogenic arrest.
Brandell et al. (1998) detected partial Y-chromosome deletions in 9 of 80 men (11%) undergoing testicular sperm extraction (TESE) due to azoospermia or cryptozoospermia. Two patients had isolated AZFc deletions with hypospermatogenesis on testicular biopsy and spermatozoa extracted by TESE. One patient with deletion of all 3 AZF regions had SCO on biopsy and TESE failed. The remaining 6 patients had deletions involving AZFb alone or AZFb and AZFc; 5 underwent testicular biopsies of which 4 revealed spermatocytic arrest and 1 hypospermatogenesis. None of the latter patients had spermatozoa extracted by TESE. Brandell et al. (1998) suggested that the presence of an AZFb deletion is a significantly adverse prognostic finding for TESE.
In a blind study, Krausz et al. (1999) screened DNA from 131 infertile males (46 idiopathic and 85 nonidiopathic) for Y-chromosome microdeletions. Of males with idiopathic infertility and an apparently normal 46,XY chromosome complement, 19% had microdeletions of either the AZFa, AZFb, or AZFc region. There was no strict correlation between the extent or location of the deletion and the phenotype. The AZFb deletions did not include the active RBM gene. Significantly, a high frequency of microdeletions (7%) was found in patients with known causes of infertility and a 46,XY chromosome complement. These included deletions of the AZFb and AZFc regions, with no significant difference in the location or extent of the deletion compared with the former group. Testicular histology was available in 6 patients, 5 of whom had large deletions in the AZFc region. On histology, 1 patient had SCO syndrome, 1 had hypospermatogenesis, 2 had premeiotic arrest, and 1 had meiotic arrest. The sixth patient had an AZFb microdeletion, with spermatogenic arrest at the spermatocyte II phase.
Foresta et al. (2001) reviewed the literature on Y-chromosome microdeletions, including published data on more than 4,800 infertile men who had been screened for Y microdeletions. Overall, the prevalence of Y-chromosome microdeletions was 4% in oligozoospermic patients, 14% in idiopathic severely oligozoospermic men, 11% in azoospermic men, and 18% in idiopathic azoospermic subjects. The authors noted that patient selection criteria appeared to substantially influence the prevalence of microdeletions. There was no clear correlation between the size and localization of the deletions and the testicular phenotype, but larger deletions were associated with the most severe testicular damage.
Madgar et al. (2002) screened 61 infertile Israeli men, 15 with severe oligospermia and 46 with azoospermia, for microdeletions of the Y chromosome involving the AZF region and for the (CAG)n repeat length of the androgen receptor (AR; 313700). Fifty fertile Israeli men were similarly analyzed. Five azoospermic men, representing 8.2% of the entire sample and 10.8% of the azoospermic subjects, displayed Y chromosome microdeletions. The mean CAG repeat number in infertile men was 18.6 compared with 16.6 in fertile men, a statistically significant difference (p = 0.003).
Foresta et al. (2005) hypothesized that infertile men may be more likely than fertile men to have genetic abnormalities. They studied 750 severely oligozoospermic men who were candidates for intracytoplasmic sperm injection and 303 fertile men. They analyzed the peripheral blood karyotype, the Y-chromosome long arm for detection of microdeletions in the azoospermia factors, and the cystic fibrosis (CFTR; 602421) and AR genes for mutations. A total of 104 genetic abnormalities were detected, corresponding to a frequency of 13.9%. Chromosomal aberrations were present in 5.6% of infertile men and 0.3% of controls, and they were in most cases alterations of the sex chromosomes. Y-chromosome long-arm microdeletions were detected in 6.0% of infertile men and most frequently included the azoospermia factor c (AZFc) region, whereas no cases were found in controls. Mutations in the CFTR gene were diagnosed in 1.2% of infertile men and 1.0% of controls, and mutations in the AR gene were found in 1.1% of infertile men and none of the 188 controls.
Over a 10-year period, Ferlin et al. (2007) studied 3,073 consecutive infertile Italian men, of which 625 had nonobstructive azoospermia and 1,372 had severe oligospermia, and identified microdeletions in 99 individuals. The prevalence of microdeletions was 3.2% in unselected infertile men, 8.3% in men with nonobstructive azoospermia, and 5.5% in men with severe oligozoospermia. Most deletions were of the AZFc-b2/b4 subtype and were associated with a variable spermatogenic phenotype, with sperm present in 72% of cases. Complete AZFa and AZFb (P5/proximal P1) deletions were associated with Sertoli cell-only syndrome and alterations in spermatocyte maturation, respectively, whereas partial deletions in these regions were associated with a milder phenotype and frequent presence of sperm. No Yq microdeletions were found in men with more than 5 million sperm/mL or in 310 controls.
AZFa Region
Sargent et al. (1999) refined the deletion breakpoints in 4 patients with AZFa male infertility. All patients had DFFRY (USP9Y; 400005) and an anonymous EST, AZFaT1, deleted in their entirety, and 3 patients also had DBY (400010) deleted. The 3 patients with AZFaT1, DFFRY, and DBY deleted showed a severe Sertoli cell-only syndrome type 1 phenotype, whereas the patient that had retained DBY showed a milder oligozoospermic phenotype. RT-PCR analysis of mouse testis RNA showed that Dby is expressed primarily in somatic cells, whereas Dffry is expressed specifically in testis in a germ cell-dependent fashion.
Sun et al. (1999) were the first to trace spermatogenic failure to a point mutation in a Y-linked gene or to a deletion of a single Y-linked gene. They sequenced the AZFa region of the Y chromosome and identified 2 previously described functional genes: USP9Y and DBY. Screening of the 2 genes in 576 infertile and 96 fertile men revealed several sequence variants, most of which appeared to be heritable and of little functional consequence. In a man with nonobstructive azoospermia, they identified a de novo mutation in USP9Y (400005.0001); the mutation was not present in his fertile brother. A testicular biopsy of the patient revealed premeiotic and meiotic germ cells in most seminiferous tubules, with small numbers of postmeiotic cells (spermatids) in a few tubules, suggesting a diagnosis of hypospermatogenesis with spermatogenic arrest. Sun et al. (1999) also identified a single gene deletion associated with spermatogenic failure, again involving USP9Y (400005.0002), by reanalyzing patient 'SAYER' reported by Brown et al. (1998); see 400042.
Foresta et al. (2000) reported a complete sequence map of the AZFa region, the genomic structure of AZFa genes, and their deletion analysis in 173 infertile men with well-defined spermatogenic alterations. Deletions were found in 9 patients: DBY alone was deleted in 6, USP9Y only in 1, and 1 each with USP9Y-DBY or DBY-UTY missing. No patients solely lacked UTY (400009). There was no clear correlation between the size and the location of the deletions and the testicular phenotype; patients lacking DBY exhibited either Sertoli cell-only syndrome or severe hypospermatogenesis. Expression analysis of AZFa genes and their X homologs revealed ubiquitous expression for all of them except DBY; a shorter DBY transcript was expressed only in testis. The authors suggested that DBY plays a key role in the spermatogenic process.
Sun et al. (2000) defined deletion breakpoints in 2 unrelated azoospermic men with AZFa deletions. In the proximal breakpoint region, they identified a 10-kb provirus of the HERV15 class of endogenous retroviruses. In the distal breakpoint region, they found a second HERV15 provirus, 94% identical in DNA sequence to the first and in the same orientation. The AZFa deletions in the 2 men differed slightly, but all breakpoints fell within the HERV15 proviruses. The authors suggested that recombination between these 2 HERV15 proviruses could account for most AZFa deletions.
Bosch and Jobling (2003) detected Y-chromosomal short tandem repeat (Y-STR) allele duplications within the AZFa region and showed that 2 chromosomes carrying these duplicated alleles contained a third junction-specific endogenous retroviral elements (HERV) sequence. Sequence analysis of these cases, which most likely represent independent duplication events, showed that breakpoints lie in the same region of inter-HERV sequence identity as do deletion breakpoints, suggesting that the mechanism of duplication is the reciprocal of the mechanism resulting in deletion. Noting the accumulated Y-STR allele diversity between duplicated copies of the AZFa region, the authors determined that one of the duplication chromosomes has been in the population for at least 17 generations, and therefore must be compatible with male fertility.
In a 42-year-old man who underwent spermatologic and genetic analysis as part of an infertility analysis after his partner had a miscarriage, Luddi et al. (2009) identified a 513,594-bp deletion in the AZFa region of the Y chromosome, with breakpoints located approximately 320,521 bp upstream and 33,465 bp downstream of the USP9Y gene (400005.0002). Spermatologic analysis revealed that total progressive motility was slightly reduced (mild asthenozoospermia), but all other sperm characteristics were within the normal range. His father and brother, who did not undergo spermatologic analysis, were also found to carry the deletion. The authors concluded that USP9Y is not essential for normal sperm production and fertility in humans.
AZFb Region
The AZFa, AZFb, and AZFc intervals were defined by interstitial Y-chromosome deletions that impair or extinguish spermatogenesis (Vogt et al., 1996). Repping et al. (2002) studied 11 unrelated azoospermic men who had previously been determined to have interstitial deletions involving AZFb, including 3 characterized as having deletions of AZFb only and 8 with deletions of AZFb plus AZFc. Using high-resolution breakpoint mapping and deletion-junction amplification and sequencing, Repping et al. (2002) found that the deletions previously thought to define the AZFb region actually extended 1.5 Mb into the AZFc region. They concluded that no distinct AZFb interval exists.
Using BAC clones, Ferlin et al. (2003) assembled a complete map of AZFb, which was estimated to extend over 3.2 Mb, with repeated sequences representing only 12% of the region. Among 700 infertile men with spermatogenic failure, Ferlin et al. (2003) found that 4 unrelated subjects (2 with a complete absence of germ cells in their testes and 2 with severe hypospermatogenesis) had partial AZFb deletions and apparently identical breakpoints. Another 8 affected men had complete AZFb deletions.
Reporting the results of a 'best practice' meeting on guidelines for the molecular diagnosis of Y-chromosome microdeletions, Simoni et al. (2004) stated that no consensus had been reached regarding the existence of a distinct AZFb region versus a model in which the AZFb and AZFc regions are overlapping.
AZFc Region
Deletions of the AZFc region of the Y chromosome are the most common known causes of spermatogenic failure. Kuroda-Kawaguchi et al. (2001) determined the complete nucleotide sequence of AZFc by identifying and distinguishing between near-identical amplicons (massive repeat units) using an iterative mapping-sequencing process. A complex of 3 palindromes, the largest spanning 3 Mb with 99.97% identity between its arms, encompasses the AZFc region. The palindromes are constructed from 6 distinct families of amplicons, with unit lengths of 115 to 678 kb, and may have resulted from tandem duplication and inversion during primate evolution. The palindromic complex contains 11 families of transcription units, all expressed in testis. For characterization of naturally occurring deletions in AZFc, Kuroda-Kawaguchi et al. (2001) studied 48 infertile men who were azoospermic or severely oligospermic (less than 5 million sperm per mL) and had interstitial Yq deletions limited to AZFc. The deletions were remarkably uniform, spanning a 3.5-Mb segment and bounded by 229-kb direct repeats that probably serve as substrates for homologous recombination.
Krausz et al. (2001) performed a double-blind molecular study of Y-chromosome deletions in 138 consecutive Danish patients seeking intracytoplasmic sperm injection treatment, 100 men of known fertility, and 107 young military conscripts from the general Danish population. No microdeletions or gene-specific deletions were detected in normospermic subjects or in subfertile men with a sperm count of more than 1x10(6)/mL. Deletions of the AZFc region were detected in 17% of individuals with idiopathic azoo/cryptozoospermia and in 7% of individuals with nonidiopathic azoo/cryptozoospermia. Krausz et al. (2001) concluded that the composition of the study population is the major factor in determining deletion frequency; Y-chromosome microdeletions are specifically associated with severe spermatogenic failure; and the frequency of Yq microdeletions in the Danish population is similar to that of other countries, suggesting that the involvement of microdeletions in the relatively low sperm count of the Danish population is unlikely.
Frydelund-Larsen et al. (2002) analyzed the serum concentrations of reproductive hormones in infertile patients with AZFc microdeletions and compared these to concentrations in a matched group of infertile patients without Yq microdeletions and to those in a group of fertile control individuals. In contrast to the study of Foresta et al. (2001) in which patients with Yq microdeletions had lower FSH (136530) and higher inhibin B (147290) plasma concentrations compared to patients without microdeletions, Frydelund-Larsen et al. (2002) found low serum inhibin B and elevated FSH levels in the majority of 16 patients with AZFc microdeletions compared with fertile control subjects, suggesting that in patients with AZF microdeletions the serum concentration of inhibin B depends upon the functional interaction between Sertoli cells and spermatocytes and/or spermatids. Bilateral testicular biopsies in 10 of the AZFc-deleted patients revealed a variable histologic pattern of severe testiculopathy: 2 patients had bilateral spermatocytic arrest and 1 had bilateral SCO syndrome; the remainder had a combination of both, and some cases showed signs of testicular atrophy. Frydelund-Larsen et al. (2002) suggested that the variable histologic picture might be related to a progressive nature of the testicular defect caused by deletion of the AZFc region.
There are rare AZFc-deleted men who have conceived multiple children naturally (Chang et al., 1999; Gatta et al., 2002). All sons of these men are infertile.
Repping et al. (2004) identified the b2/b3 deletion, a recurrent 1.8-Mb deletion that removes half of the AZFc region, including 12 members of 8 testis-specific gene families. Deleted genes include RBMY1A1, BPY2 (400013), DAZ, CDY1 (400016), PRY (400019), CSPG4LY (400034), GOLGA2LY (400035), TTTY3 (400036), TTTY4 (400037), TTTY5 (400038), TTTY6 (400039), and TTTY17 (400040). The authors found the deletion primarily in branch N in the Y-chromosome genealogy, in which all chromosomes carried the deletion. Branch N is widely distributed in northern Eurasia, accounts for the majority of Y chromosomes in some populations, and appears to be several thousand years old. The deletion has at most a modest effect on fitness, either because it spares at least 1 near-identical copy of each gene family, or because it has been counterbalanced by another genetic factor.
To determine the incidence of various partial AZFc deletions and their effect on fertility, Machev et al. (2004) discriminated 4 types of DAZ-CDY1 partial deletions and performed combined quantitative and qualitative analyses of the AZFc region in 300 infertile men and 399 controls. Only one deletion type, DAZ3/4 (400027, 400048)-CDY1a (400016), was associated with male infertility (p = 0.042), suggesting that most of the partial deletions are neutral variants. A stronger association, however, was found between loss of the CDY1a sequence family variant (SFV) and infertility (p = 0.002). Machev et al. (2004) concluded that loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.
Using AZFc-specific STS markers and DAZ-specific single nucleotide variants, Ferlin et al. (2005) studied 337 infertile men with different impairments of spermatogenesis and 263 normozoospermic fertile men. The authors identified 18 cases of partial AZFc deletions in the infertile group (5.3%) and 1 case in the control group (0.4%); 17 deletions had the so-called gr/gr pattern, 1 had the b2/b3 pattern, and 1 represented a novel deletion with breakpoints in the b3 and b4 amplicons. A father and 5 sons who had apparently identical gr/gr deletions with loss of DAZ3/DAZ4 had very different seminal patterns, ranging from moderate oligospermia to azoospermia, and the normozoospermic man with a partial AZFc deletion also had a gr/gr pattern with loss of DAZ3/DAZ4. Analysis of DAZ gene copy number in this study together with published data led Ferlin et al. (2005) to suggest that only partial AZFc deletions removing DAZ1/DAZ2 (400003, 400026) are associated with spermatogenic impairment, whereas those removing DAZ3/DAZ4 may have little or no effect on fertility.
Giachini et al. (2005) analyzed 150 oligo- and azoospermic men and 189 normospermic controls and identified 2 types of partial AZFc deletions, gr/gr and b2/b3. The frequency of gr/gr deletions was significantly higher in the infertile group than controls (5.3% vs 0.5%, p less than 0.012), whereas the frequency of the b2/b3 was not different between the 2 groups. Gene-specific analysis revealed 3 distinct deletion patterns; the authors suggested that combined studies based on gene copy and haplotype analysis might distinguish pathogenic from neutral deletions.
In epidemiologic studies, male infertility has shown an association with testicular germ cell tumor (TGCT; 273300). Since the gr/gr deletion is associated with infertility, Nathanson et al. (2005) postulated an association between the gr/gr deletion and TGCT. They analyzed this deletion in a large series of TGCT cases with or without a family history of TGCT. The gr/gr deletion was present in 3% of TGCT cases with a family history, 2% of TGCT cases without a family history, and 1.3% of unaffected males. Presence of the gr/gr deletion was associated with a 2-fold increased risk of TGCT and a 3-fold increased risk of TGCT among patients with a positive family history. The gr/gr deletion was more strongly associated with seminoma TGCT than with nonseminoma TGCT. The data indicated that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.
Arredi et al. (2007) analyzed 8 Y-chromosome haplogroups in 41 unrelated infertile Italian males with the AZFc b2/b4 deletion and 93 Italian men with at least 1 child and no microdeletion. They found that men with microdeletions had a significantly higher frequency of the E haplogroup (29.3% vs 9.7%, p less than 0.01). The authors concluded that Y-chromosome background affects the occurrence of AZFc b2/b4 deletions in this population.
Lin et al. (2007) screened 580 Han Chinese in Taiwan for AZFc deletion and duplication and found that 9.5% had AZFc partial deletion, 2.7% had partial deletion followed by duplication, and 1.7% had partial duplication. Rearrangement frequencies varied significantly between different Y-chromosome haplogroups, ranging from 2.9% in O3e to 100% in N and Q. Additional screening in 142 oligospermic men and 107 fertile controls found no significant differences in gr/gr or b2/b3 deletion; however, the frequency of AZFc partial duplication in the infertile group was significantly higher than that in the fertile control group (7.0% vs 0.9%, p = 0.0031). Lin et al. (2007) concluded that AZFc partial deletion and partial duplication are common polymorphisms in Han Chinese, and that AZFc partial duplication, but not AZFc partial deletion, is a risk factor for male infertility in the Taiwanese population.
Zhang et al. (2007) typed complete and partial AZFc deletions as well as 19 binary haplogroup markers in 296 Chinese men with spermatogenic impairment and 280 healthy controls. Haplogroup Q1 was found to be gr/gr-deleted, and fixation of the b2/b3 deletion was confirmed in haplogroup N. AZFc partial deletions were not associated with spermatogenic failure in this population, suggesting phenotypic variation of partial AZFc deletions across populations.
Giachini et al. (2008) screened 556 infertile Italian men and 487 normozoospermic controls for partial AZFc deletions using sequence-tagged site (STS) analysis followed by CDY1-DAZ gene dosage and copy number analysis, and found that the frequency of gr/gr deletions in patients was significantly different from controls (p less than 0.001; odds ratio, 7.9); however, the authors did not detect a significant effect of b2/b3 deletions or partial AZFc duplications on spermatogenesis in their population.
In 160 European men with confirmed gr/gr deletions, including 16 fertile or normospermic men, 26 with azoospermia, 93 with crypto- or oligozoospermia, and 14 with astheno- and/or teratozoospermia, Krausz et al. (2009) analyzed known AZFc structural variants associated with this deletion and Y-SNP-defined haplogroup chromosome background, but found that none of these factors accounted for a significant proportion of the spermatogenic variation associated with gr/gr deletions. The authors concluded that the phenotypic variation of gr/gr deletion carriers in men of European background is largely independent of the Y-chromosomal background.
Noordam et al. (2011) analyzed the presence or absence of STS markers in 840 men who were each part of a subfertile couple, unselected for sperm count. Thirty-one men (3.7%) had deletion of 1 or more STS markers: 22 had gr/gr deletions, 4 had b2/b4 deletions, 4 had b2/b3 deletions, and 1 had a b1/b3 deletion. Using real-time quantitative PCR, Noordam et al. (2011) determined actual copy numbers of the DAZ, BPY2, CDY1, CSPG4LY, and GOLGA2LY genes in the 31 men with partial AZFc deletions. For all AZFc genes, they found an association between a reduction in the copy number of each individual AZFc gene and reduced total motile sperm count (TMC). In gr/gr-deleted men, restoration of reduced gene copy numbers via secondary duplication restored their TMC to normal values. Noordam et al. (2011) suggested that the gene content of the AZFc region has been preserved throughout evolution through a dosage effect of the AZFc genes on TMC, safeguarding male fertility.
Rozen et al. (2012) screened 20,884 anonymized DNA samples from men of 5 populations (India, Poland, Tunisia, United States, and Vietnam) for 6 recurrent interstitial deletions in the AZFc region, and found that 1 of every 27 men carried 1 of 4 deletions: gr/gr, b2/b3, b1/b3, and b2/b4, in descending order of prevalence. The 1.6-Mb gr/gr deletion, found in 2.4% of the men, almost doubled the risk of severe spermatogenic failure (SSF), defined as a sperm count of less than 5 million per milliliter of semen in the absence of physical obstruction. The gr/gr deletion accounted for approximately 2.2% of SSF, although less than 2% of men with the deletion were affected. The 1.8-Mb b2/b3 deletion, found in 1.1% of men, did not appear to be a risk factor for SSF. The 1.6-Mb b1/b3 deletion, found in 0.1% of men, appeared to increase the risk of SSF by a factor of 2.5, although less than 2% of men with the deletion were affected and it accounted for only 0.15% of SSF. The 3.5-Mb b2/b4 deletion, present in 0.043% of men, was associated with a 145-fold increase in the risk of SSF and accounted for approximately 6% of SSF. Rozen et al. (2012) concluded that a single rare variant of major effect, the b2/b4 deletion, and a single common variant of modest effect, the gr/gr deletion, are largely responsible for the contribution of the ACFc region to severe spermatogenic failure.
AZFd Region
Kent-First et al. (1999) designed a panel of 9 multiplexed reactions, including 48 Y-linked STSs, for the identification of infertility-associated microdeletions of the Y chromosome. They identified a fourth AZF region required for normal spermatogenesis, located between AZFb and AZFc, which they designated AZFd.
Reporting the results of a 'best practice' meeting on guidelines for the molecular diagnosis of Y-chromosome microdeletions, Simoni et al. (2004) stated that the sequence of the male-specific portion of the Y chromosome (MSY) and the mechanism underlying the microdeletions have shown definitely that the putative fourth AZFd region postulated by Kent-First et al. (1999) does not exist.
Y-Chromosome Haplogroups
Krausz et al. (2001) typed the Y chromosome in a group of oligo- or azoospermic Danish men who had previously been shown (Krausz et al., 2001) not to harbor microdeletions in the AZFa, b, or c regions and compared the haplotype distribution with that of a group of unselected Danish males. One class of Y chromosome, referred to as haplogroup 26+, was significantly overrepresented (27.9%; p less than 0.001) in the group of men with either idiopathic oligozoospermia (defined as less than 20 million sperm/mL) or azoospermia compared to the control Danish male population (4.6%). The authors hypothesized that since this class of Y chromosome may be at risk for infertility among Danish men, active selection against such a haplotype could alter the pattern of Y-chromosome haplotype distribution in the general population.
Carvalho et al. (2003) analyzed 84 Japanese oligo- or azoospermic men for Yq microdeletions and also defined their Y haplogroups using a battery of unique event polymorphisms. In the 6 infertile men in whom likely pathologic microdeletions were found, there was no significant association between Y-chromosome haplogroups and the microdeletions. Carvalho et al. (2003) also compared the Y-haplogroup frequencies in a subset sample of 51 patients with idiopathic azoospermia to those in 57 fertile control Japanese males and observed no significant differences. The authors concluded that Y microdeletions and other molecular events associated with male infertility in Japan occur independently of Y-chromosome background.
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