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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Y Chromosome Infertility

Synonym: Y Chromosome-Related Azoospermia

, MD and , PhD.

Author Information
, MD
Infertility Center of St. Louis
St. Luke’s Hospital
St. Louis, Missouri
, PhD
Pathology and Medicine Departments
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: October 18, 2012.

Summary

Disease characteristics. Y chromosome infertility is characterized by azoospermia (absence of sperm), severe oligozoospermia (<1 x 106 sperm/mL semen), moderate oligozoospermia (1-5 x 106 sperm/mL semen), or mild oligozoospermia (5-20 x 106 sperm/mL semen). Males with Y chromosome infertility usually have no obvious symptoms, although physical examination may reveal small testes.

Diagnosis/testing. The diagnosis of Y chromosome infertility is suspected in otherwise healthy males with azoospermia or oligozoospermia and/or abnormal sperm morphology/motility for whom other causes of infertility have been eliminated. Chromosomal microarray (CMA) or routine cytogenetic testing reveals chromosome abnormalities in 5%-10% of these men. Molecular testing reveals microdeletions of the long arm of the Y chromosome in another 5%-13% of these males.

Management. Treatment of manifestations: Pregnancies may be achieved by in vitro fertilization using ICSI (intracytoplasmic sperm injection), an in vitro fertilization procedure in which spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with azoospermia) are injected into an egg harvested from the reproductive partner.

Other: Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been successful for most males with AZFc deletions; in males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on the fertilization or pregnancy rates; the risk for birth defects is the same as for any infertile couple who achieves a pregnancy using assisted reproductive technology.

Genetic counseling. Y chromosome infertility is inherited in a Y-linked manner. Because males with Y chromosome deletions are infertile, the deletions are usually de novo and therefore not present in the father of the proband. Despite their severely impaired spermatogenesis, some males with deletion of the AZF regions have occasionally spontaneously fathered sons who are infertile. This will occur in about 4% of couples with severe oligospermia if the female partner is young and very fertile. In pregnancies achieved using ICSI, male offspring have the same deletion as their father, with a high risk of male infertility. Note that certain Y deletions, including the most common Y deletions (gr/gr), do not necessarily cause infertility, but are only a risk factor for infertility. Female fetuses from a father with a Y chromosome deletion have no increased risk of congenital abnormalities or infertility. In pregnancies conceived through assisted reproductive technology (ART) and known to be at risk of resulting in a male with Y chromosome deletion, specific prenatal testing or preimplantation testing could be performed to determine the sex of the fetus and/or the presence of the Y chromosome deletion.

Diagnosis

Clinical Diagnosis

Males with Y chromosome infertility usually have a normal physical examination, although some have small testes.

Other causes of male infertility need to be excluded (see Differential Diagnosis).

Note that the clinical literature on Y deletions can be very confusing, leading to misconceptions about the phenotypic effects of the deletions. The soundest literature on this subject is exhaustively cited in the 2011 review of one of the authors [Silber 2011].

Semen analysis. Ejaculate is examined to determine the number, motility, and morphology of sperm. Semen analysis should follow the WHO guidelines, Laboratory Manual for the Examination and Processing of Human Semen [WHO 2010]. The following categories of sperm count are identified (Table 1):

Table 1. Classification of Sperm Count

Classification of Sperm Count 1 Sperm Count in Millions/mL
Azoospermia0
Severe oligozoospermia<1
Moderate oligozoospermia 1-5
Mild oligozoospermia 5-20
Normal>20

1. In each category, the morphology and/or motility of the sperm can be normal or abnormal (asthenoteratozoospermia).

Testing

Chromosome microarray (CMA). CMA testing performed on peripheral blood can detect chromosomal imbalances including aneuploidy (e.g. 47,XXY) as well as deletions or duplications of the Y chromosome, provided that the abnormal regions are covered by informative probes. This analysis complements and confirms the molecular genetic testing. Note that interpretation of CMA data for the detection of Y deletions can occasionally be complicated by the fact that many of the genes implicated in Y infertility are present in multiple copies with similar sequences. Although balanced chromosomal rearrangements are not detected by CMA, copy number changes in addition to those relevant to infertility can be detected, for example deletion of SHOX, which is important for medical management [Jorgez et al 2011].

Cytogenetic analysis. Approximately 5%-10% of men with unexplained infertility associated with azoospermia/oligozoospermia and/or anomalies of sperm morphology/motility have chromosome abnormalities, mostly gonosomal (i.e., involving the sex chromosomes) but also autosomal. Abnormalities can be numerical (e.g., Klinefelter syndrome 47,XXY) or structural (e.g., balanced autosomal translocation). Routine cytogenetic studies including G-banding and fluorescence in situ hybridization (FISH) analyses using probes specific for Y-linked genes performed on peripheral blood can detect the following Y chromosome structural abnormalities, when present:

  • Terminal deletions of Yq that include the heterochromatic band Yq12 at the end of the long arm of the Y chromosome. Note that pseudodicentric Y chromosomes may be incorrectly classified as terminal deletions.
  • Other more complex Y chromosome rearrangements that lead to long arm deletions. For example, a pseudodicentric Y chromosome (also called isodicentric or "non-fluorescent Y") results in both deletion of part of the Y long arm and duplication of the Y short arm and proximal Y long arm. The detection of complex Y chromosome rearrangements is important because some (e.g., pseudodicentric Y chromosomes and ring Y chromosomes) are often associated with a 45,X cell line [Lange et al 2009]. Furthermore, complex Y chromosome rearrangements can lead to disruption of genes within the pseudoautosomal region (PAR), for example SHOX, and to additional phenotypes including short stature [Jorgez et al 2011].

However, cytogenetic analysis alone cannot:

  • Detect microdeletions or micoduplications of the Y chromosome;
  • Determine whether a cytogenetically visible deletion extends into the AZF regions.

Testicular biopsy. Testicular biopsy may reveal either one of the following:

  • Sertoli-cell-only syndrome (SCOS), in which azoospermia is associated with the absence of or only occasional germ cells in tubules that for the most part have only Sertoli cells lining them with no or rare spermatogenesis
  • Maturation arrest with spermatocytes but no spermatids or mature sperm

Molecular Genetic Testing

Genes. Y chromosome infertility may be caused by either of the following:

  • Microdeletions or rearrangements (e.g., a pseudodicentric Y chromosome; see Testing, Cytogenetic analysis) of the long arm of the Y chromosome (Yq) in the AZF regions (see Figure 1) associated with deletion of multiple genes
  • A rare single gene abnormality of USP9Y in AZFa region
Figure 1

Figure

Figure 1. Schematic of the Y chromosome indicating the approximate position of the previously defined regions AZFa, AZFb, and AZFc and the position of recurrent deletions currently defined on the basis of the flanking palindromic repeats (see Table 2) (more...)

Clinical testing

  • Deletion/duplication analysis. The molecular diagnosis of Y chromosome deletion consists of a series of PCR (polymerase chain reaction) amplifications within relatively broad regions of the Y chromosome. Interstitial Yq microdeletions can remove various portions of the long arm, depending on breakpoints. Specific genes (i.e., USP9Y, DDX3Y, BPY/VCY, HSFY1, HSFY2, KDM5D, RPS4Y2, RBMY, PRY, DAZ, and CDY; see Molecular Genetics) located along the Y chromosome should be included in the analysis to assess Y chromosome integrity. Deletion/duplication analysis (e.g., quantitative PCR) can help to determine the number of gene copies [Noordam et al 2011].

    Note: (1) Although guidelines for testing (including the use of positive and negative control samples for PCR analysis) have been published [Simoni et al 2004], the testing recommended is often insufficient, especially with regard to specific genes that should be included. (2) Commercial kits have been designed but need further evaluation [Aknin-Seifer et al 2005].
  • Originally, three AZF regions were defined: AZFa, AZFb, and AZFc (azoospermia factors a, b, and c), which map on the long arm (Yq) in order from the centromere to the telomere and were thought to be non-overlapping. However, subsequent studies showed that AZFb and AZFc overlap [Repping et al 2002] (see Figure 1 and Molecular Genetics). Because the deletions tend to occur between large palindromic repeats, a more appropriate nomenclature for the types of recurrent deletions is to use the name of the flanking repeats [Yen 2001, Repping et al 2002].
  • Single gene defects. Many genes implicated in Y infertility are multi-copy and thus very difficult to test by sequence analysis. A few genes in AZFa (USP9Y, and DDX3Y) are single-copy and thus amenable to sequence analysis to detect small intragenic mutations (e.g., missense, nonsense). These types of mutations are not detectable by deletion/duplication analysis and thus require other types of testing (e.g., sequence analysis). Mutations involving USP9Y, located in the AZFa region (see Figure 1), have been reported in rare cases [Sun et al 1999]. However, complete deletion of USP9Y has been found in fertile individuals (albeit with reduced spermatogenesis), and severely impaired spermatogenesis only occurs when both USP9Y and DDX3Y are deleted [Luddi et al 2009].

Table 2. Summary of Molecular Genetic Testing Used in Y Chromosome Infertility

Gene SymbolTest MethodGenetic MechanismPhenotypeMutation Detection Frequency 1
N/ADeletion /
duplication analysis 2
Interstitial AZFa deletion
(HERV15yq1-HERV15yq2) 3
SCOSRare
Interstitial AZFc
deletion (b2/b4) 3
Oligozoospermia6%
Azoospermia13%
Interstitial AZFb and AZFb+c deletions (P5/proxP1, P5/distP1, P4/distP1) 3 Azoospermia1%-2%
Terminal AZFdeletion (often representing a pseudodicentric Y chromosome with duplication and deletion) AzoospermiaRare
USP9YDirect DNA 4Sequence variants in AZFaHypospermatogenesisRare 5
DDX3YDirect DNA 4Sequence variants in AZFa 6Azoospermia if both DDX3Y and USP9Y are deletedRare

SCOS = Sertoli-cell-only syndrome

ND = No data

1. Incidence of deletions or mutations caused by the genetic mechanism listed in males with infertility

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

3. Indicates the flanking repeats [Kamp et al 2000, Sun et al 2000, Kamp et al 2001, Yen 2001, Oates et al 2002, Repping et al 2002]

4. “Direct DNA” is a term used in GeneReviews to refer to methods used in research testing that may include any combination of targeted mutation analysis, mutation scanning, sequence analysis, deletion/duplication testing or other means of molecular genetic testing.

5. Intragenic mutations involving USP9Y, located in the AZFa region (see Figure 1) have been reported in rare cases [Sun et al 1999]. These types of mutations are not detectable by deletion/duplication analysis and thus require other types of testing (e.g., sequence analysis).

6. No point mutations or other small intragenic mutations in DDX3Y have been reported as a cause of Y chromosome infertility.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband. Sperm counts and morphology/motility should be assessed and molecular genetic testing done using deletion/duplication analysis. If no deletion is found, CMA analyses using an array with sufficient coverage of the Y chromosome (to detect copy number changes) should be performed. If no abnormality is found, routine cytogenetic studies should be performed to detect balanced chromosomal rearrangements. If necessary, cytogenetic analysis using G-banding, Q-banding, and FISH employing specific Y probes should be done to clarify a complex rearrangement.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion of the AZF region(s) of the long arm of the Y chromosome.

Clinical Description

Natural History

Males with Y chromosome infertility usually have no obvious symptoms, although physical examination may reveal small testes. Males with Y chromosome infertility have azoospermia or severe, moderate, or mild oligozoospermia (Table 1). Oligozoospermia may be compatible with fertility in some instances.

Short stature may occur in individuals with Yq deletions that extend close to the centromere in a region containing a putative growth-controlling gene, GCY [Kirsch et al 2002, Kirsch et al 2004]. Abnormal stature may also be caused by hidden copy number changes within the pseudoautosomal region (PAR), which may affect SHOX [Jorgez et al 2011]. However these conditions are rare and deletions limited to the AZF regions are not associated with any phenotypic abnormalities other than infertility.

Genotype-Phenotype Correlations

Each AZF region contains several genes that play a role in different stages of spermatogenesis. It is likely that future analysis of these individual genes in infertile males will result in more precise genotype-phenotype correlations. However, the multi-copy and polymorphic nature of most fertility genes located on the Y chromosome makes it difficult to define their role precisely.

The regions initially defined as AZFb and AZFc have been found to partially overlap (Figure 1) [Repping et al 2002]. Much of the literature still refers to these regions; thus, the authors include reference to these regions by the palindromic repeats that now define the deletions more precisely [Silber 2011].

  • Interstitial or terminal deletions that include all of AZFa are rare and usually produce the severe phenotype of Sertoli-cell-only syndrome (SCOS) [Silber 2011] (see Differential Diagnosis). The interstitial deletions are mediated by recombination between the HERV15yq1-HERV15yq2 repeats. One single-copy gene (USP9Y) located in AZFa has been directly implicated in the infertility phenotype, following detection of a point mutation and a deletion limited to this gene in two infertile males with hypospermatogenesis but without SCOS [Sun et al 1999]. Complete deletion of USP9Y has been found in fertile individuals, albeit with hypospermatogenesis [Luddi et al 2009], suggesting that SCOS usually associated with AZFa deletion is not caused by USP9Y deletion alone but must include deletion of at least one adjacent gene, DDX3Y, to result in azoospermia. Complete AZFa deletions thus involve loss of two genes, USP9Y and DDX3Y, and result in a much more severe phenotype than mutation of USP9Y alone.
  • Interstitial or terminal deletions that include AZFb and/or AZFb+c (hereafter designated AZFb/c) are mediated by recombination between palindromic repeats, either P5/proxP1, P5/distP1, or P4/distP1. These deletions are uncommon and usually result in severe azoospermia [Repping et al 2002, Silber 2011]. Partial deletion of AZFb that removes the entire P4 palindrome decreases spermatocyte maturation but can be transmitted [Kichine et al 2012].
  • Interstitial or terminal deletions that include AZFc only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable infertility phenotype, ranging from azoospermia and SCOS to severe or mild oligozoospermia [Oates et al 2002, Silber 2011]. This type of deletion is common.
  • Two partial deletions of AZFc, called b1/b3, b2/b3 are considered to represent benign copy number variants (polymorphisms) [Repping et al 2003, Fernandes et al 2004, Machev et al 2004, Ferlin et al 2007]. Another partial deletion, gr/gr, may have some impact on fertility depending on ethnicity and geographic region [Stouffs et al 2011]. Males with gr/gr deletions can also have compensatory duplications of genes [Noordam et al 2011].
  • Duplication of the AZFa or AZFc regions has been reported and does not appear to be associated with an abnormal phenotype [Bosch & Jobling 2003, Giachini et al 2008].

Penetrance

Rarely within a family, the same deletion of the Y chromosome has been reported to occasionally cause infertility in some males but not in others [Chang et al 1999, Saut et al 2000, Gatta et al 2002, Repping et al 2003]. These observations have been misinterpreted as representing variable penetrance. However, they result from the fact that even a severely oligospermic male with a Y chromosome deletion in the AZF regions can occasionally impregnate a very fertile partner.

Prevalence

The prevalence of Y chromosome deletions and microdeletions is estimated at one in 2000 to one in 3000 males.

The frequency of Yq microdeletions in males with azoospermia or severe oligozoospermia is about 5%-15% [Vogt 1997, Silber et al 1998, Oates et al 2002, Silber 2011].

Differences in prevalence based on ethnicity have not been observed. However, the gr/gr deletion may have a different impact on fertility depending on ethnicity and geographic region [Stouffs et al 2011]. Deletions gr/gr are extremely common (25%) in Japanese men, for example, and represent simply a “risk factor” for male infertility.

Differential Diagnosis

Infertility affects 15%-20% of couples of reproductive age. Infertility is thought to be male related in about half of those couples, but this often-quoted figure is poorly documented. Most likely, oligospermia sufficiently severe to cause infertility would only be present in 10% of infertile couples. Causes of male infertility other than deletion of the Y chromosome are numerous and often controversial. In most cases, male infertility is of unknown etiology. Possible causes of male infertility other than Y chromosome deletion include the following conditions:

  • Obstruction of the ejaculatory ducts, which should be evaluated by physical examination [Practice Committee of the American Society for Reproductive Medicine 2004]. Congenital bilateral absence of the vas deferens (see CFTR-Related Disorders) should be considered in this evaluation. CFTR-related disorders include cystic fibrosis (CF) and congenital bilateral absence of the vas deferens (CBAVD). All males with CF are infertile as a result of azoospermia caused by absent, atrophic, or fibrotic Wolffian duct structures. CBAVD more commonly occurs in men without pulmonary or gastrointestinal manifestations of CF who have one allele with a severe CFTR mutation and another allele with a mild T5 mutation. These men still make about 10% of the normal amount of CTFR protein, which is enough to prevent clinical CF, but not enough to allow fetal Wolffian duct development [Chillon et al 1995]. Affected men have azoospermia and are thus infertile. CF is inherited in an autosomal recessive manner.
  • Immunologic abnormalities caused by anti-sperm antibodies (controversial)
  • Infection (e.g., mumps orchitis, epididymitis, urethitis); can generally be differentiated from Y chromosome infertility by past history and is uncommon
  • Vascular abnormalities (varicocele); may be identified on physical examination, but their relevance to male infertility has been robustly questioned by most reproductive endocrinologists and is very controversial [Silber 2001].
  • Trauma (distinguished by history and very rare)
  • Endocrine abnormalities; also rare (for example, congenital adrenal hyperplasia, isolated follicle-stimulating hormone (FSH) deficiency, and hyperprolactinemia). These can be differentiated through hormone studies. Kallmann syndrome (KS), the association of isolated GnRH deficiency (IGD) and anosmia (absence of smell), needs to be considered. Some males with KS have micropenis and cryptorchidism as neonates. Adults with KS have incomplete development of secondary sexual characteristics and prepubertal testicular volume (i.e., <4 mL). KAL1 and FGFR1 are the only two genes known to be associated with Kallmann syndrome. Together, mutations in the two genes account for approximately 15%-25% of KS. Non-reproductive phenotypes:
    • In males with KAL1 mutations. Synkinesia (mirror movement) of the digits, unilateral renal agenesis, sensorineural hearing loss, high-arched palate
    • In males with FGFR1 mutations. Synkinesia of digits, cleft lip and/or palate, dental agenesis, brachydactyly or syndactyly, corpus callosum agenesis
  • Testicular tumor, or other tumor caused by exposure to toxic agents
  • Exposure to toxic agents such as radiation, chemotherapy, heat exposure (evaluated by full medical history)
  • Klinefelter syndrome (XXY), which can be detected by cytogenetic analyses or CMA in men with non-obstructive azoospermia and oligospermia and accounts for approximately 4% of azoospermic men.
  • Balanced chromosomal rearrangements, which can be detected by cytogenetic evaluation in about 1.5% of men with non-obstructive azoospermia and oligospermia. In this case, there may also be a family history of multiple miscarriages and/or various phenotypic anomalies.

Sertoli-cell-only syndrome (SCOS) is the term applied to the finding of germinal aplasia in males. It has numerous causes including Y deletion, exposure to toxic chemotherapy agents or irradiation, mumps orchitis, Down syndrome, Klinefelter syndrome (47,XXY), congenital adrenal hypoplasia, isolated follicle-stimulating hormone (FSH) deficiency, and hyperprolactinemia. For each of these, the medical history, the presence of other anomalies or symptoms, or chromosome analysis should differentiate them from Y chromosome infertility. In most cases, the etiology of SCOS is unknown.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Y chromosome infertility, semen analysis to determine the number, motility, and morphology of sperm is recommended.

Treatment of Manifestations

A couple in which the male has Y chromosome infertility can be offered the option of in vitro fertilization using ICSI (intracytoplasmic sperm injection) [Silber 2011]. In this procedure, spermatozoa retrieved from ejaculate (in males with oligozoospermia) or extracted from testicular biopsies (in males with azoospermia) are injected into a harvested egg by IVF (in vitro fertilization).

Retrieval of sperm has been successful mainly for most males with deletions of AZFc, and rarely for males with deletions of AZFb or AZFa. The reason for this is that an autosomal copy of DAZ (DAZL) may serve as a “back up gene,” which would help preserve a tiny amount of residual spermatogenesis in males with AZFc deletions that remove the DAZ genes. There are no such autosomal “back up” copies for genes in AZFa and AZFb.

The definition of SCOS (Sertoli cell only syndrome) has been the subject of confusion in the literature. There are two main causes of non-obstructive azoospermia (NOA): maturation arrest and Sertoli cell only. With maturation arrest, there is a failure of spermatocytes to progress beyond meiosis I. But in 60% of cases, a few spermatocytes do progress to sperm and can be retrieved from the testis. Similarly, in about 60% of cases with SCOS a tiny number of tubules actually contain a few spermatozoa resulting from small foci of spermatogenesis.

It is important to discuss the possibility of transmission of Y chromosome infertility to male offspring (see Genetic Counseling) prior to attempting fertilization by ICSI and IVF [Stouffs et al 2005].

In males with retrievable spermatozoa, the presence or absence of deletion of the long arm of the Y chromosome has no apparent effect on fertilization or pregnancy rates [Oates et al 2002, Kihaile et al 2004, Silber 2011]. The risk for birth defects is not different from that of any infertile couple who achieves a pregnancy through assisted reproductive technology [Choi et al 2004, Davies et al 2012].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Testicular sperm retrieval for in vitro fertilization is ineffective for males with AZFb and AZFa deletions, but has been achieved for the majority of males with AZFc deletions [Oates et al 2002, Stouffs et al 2005, Reyes-Vallejo et al 2006, Silber 2011].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Y chromosome infertility is inherited in a Y-linked manner.

Risk to Family Members

Parents/father of a proband

  • Because males with deletion of the AZF regions of the long arm of the Y chromosome are infertile, the deletions are usually de novo and therefore not present in the father of the proband, except for gr/gr, which can be inherited and have a variable phenotype.
  • Rarely within a family, a male with an AZFc deletion of the Y chromosome has fathered a son, who is infertile [Chang et al 1999, Saut et al 2000, Gatta et al 2002, Repping et al 2003]. However, it should be stressed that in these families, the fathers with an AZFc deletion were all severely oligospermic, but had a young and very fertile partner who conceived despite her partner's low sperm count.
  • Men with gr/gr deletions have variable fertility, and can readily transmit the deletion to future generations [Silber 2011]. Deletions of b1/b3 and b2/b3 are inconsequential, and have no effect on male fertility.

Sibs/brothers of a proband

  • Because a Y chromosome deletion found in an infertile male is usually de novo, the risk to the brothers of a proband is very low.
  • On very rare occasions, the brothers of a proband may be at risk because within a family the same deletion of the AZFc region may appear to result in infertility in some individuals but not in others [Chang et al 1999, Saut et al 2000, Repping et al 2003]. However, it should be made clear again that all men with the AZFc deletion have a severe spermatogenic defect, which is only rarely compensated for by high fertility in their partner. In individuals with a gr/gr deletion fertility is variable.

Offspring of a proband

Other family members. It is unlikely that extended family members are at increased risk for Y chromosome infertility since Y chromosome deletions are de novo events that occur in 1/2000 sperms in the testis of a father with normal spermatogenesis. Furthermore, the possibility of transmission of AZF deletions is extremely remote.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies conceived through assisted reproductive technology (ART) and at risk of resulting in a male with Y chromosome deletion is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). Testing includes determining the sex of the fetus and/or the presence of a Y chromosome deletion. Prenatal diagnosis is also possible for pregnancies at risk for chromosome abnormalities (e.g., 45,X mosaicism) resulting from a paternal Y chromosome rearrangement (e.g., pseudodicentric Y or ring Y).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some pregnancies conceived through assisted reproductive technology (ART) and at risk of resulting in a male with Y chromosome deletion.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • InterNational Council on Infertility Information Dissemination, Inc. (INCIID)
    PO Box 6836
    Arlington VA 22206
    Phone: 703-379-9178
    Fax: 703-379-1593
    Email: inciidinfo@inciid.org
  • RESOLVE: The National Infertility Association
    1760 Old Meadow Road
    Suite 500
    McLean VA 22102
    Phone: 703-556-7172
    Fax: 703-506-3266
    Email: info@resolve.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Y Chromosome Infertility: Genes and Databases

Chromosome RegionGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
AZFaNot applicableYq11​.2Not applicable
AZFbNot applicableYq11​.2Not applicable
AZFcNot applicableYq11​.2Not applicable
USP9YYq11​.21Probable ubiquitin carboxyl-terminal hydrolase FAF-YUSP9Y homepage - Mendelian genesUSP9Y

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Y Chromosome Infertility (View All in OMIM)

400003DELETED IN AZOOSPERMIA; DAZ
400005UBIQUITIN-SPECIFIC PROTEASE 9, Y CHROMOSOME; USP9Y
400006RNA-BINDING MOTIF PROTEIN, Y CHROMOSOME, FAMILY 1, MEMBER A1; RBMY1A1
400010DEAD/H BOX 3, Y-LINKED; DDX3Y
400012VARIABLY CHARGED, Y CHROMOSOME; VCY
400013BASIC PROTEIN, Y CHROMOSOME, 2; BPY2
400015XK-RELATED PROTEIN ON Y CHROMOSOME
400016CHROMODOMAIN PROTEIN, Y CHROMOSOME, 1; CDY1
400018CHROMODOMAIN PROTEIN, Y CHROMOSOME, 2; CDY2
400019PTPBL-RELATED GENE ON Y; PRY
400026DELETED IN AZOOSPERMIA 2; DAZ2
400027DELETED IN AZOOSPERMIA 3; DAZ3
400029HEAT-SHOCK TRANSCRIPTION FACTOR, Y-LINKED; HSFY
400030RIBOSOMAL PROTEIN S4, Y-LINKED, 2; RPS4Y2
400041PTPBL-RELATED GENE ON Y, 2; PRY2
400042SPERMATOGENIC FAILURE, Y-LINKED, 1; SPGFY1
415000SPERMATOGENIC FAILURE, Y-LINKED, 2; SPGFY2
426000LYSINE-SPECIFIC DEMETHYLASE 5D; KDM5D

Molecular Genetics of Y Chromosome Infertility

  • Click here to view the Y chromosome using the NCBI Map Viewer. Use the Zoom feature at left to see the complete list of genes.
  • For a list of gene symbols and descriptions by cytogenetic location, click here.

Molecular Genetic Pathogenesis

Locus symbols. Originally, three azoospermia regions (a, b, and c) were defined as AZFa, AZFb, and AZFc. However, because AZFb and AZFc overlap, a new nomenclature was developed to distinguish deletions based on the flanking palindromic repeat names [Repping et al 2002, Silber 2011]. It is likely that additional deletion types will be discovered (see Table 2).

Gene symbols. For a listing of genes located on the long arm of the Y chromosome, refer to NCBI, where the functional annotation of the genes is kept current.

Chromosomal locus. The male infertility phenotype maps to relatively broad regions defined on the Y chromosome (Figure 1). The regions have been defined on the basis of deletion intervals found in infertile males. These massive interstitial deletions are mediated by recombination between palindromic repeats on the Y chromosome.

AZFa is 792 kb long and just distal to the centromere of the Y chromosome (Figure 1) [Kamp et al 2001]. Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences located around AZFa has been identified as the mechanism that generates AZFa deletions [Kamp et al 2000, Sun et al 2000, Kamp et al 2001].

AZFb and AZFc overlap, with distal AZFc located just proximal to the Y chromosome heterochromatic band Yq12 (Figure 1). The most common Y chromosome deletion, formerly known as AZFc deletion, removes 3.5 Mb between palindromes b2 and b4 [Kuroda-Kawaguchi et al 2001, Vogt 2005]. Two of the largest interstitial deletions in the AZFb/c region remove either 6.2 Mb between palindromes P5 and proximal P1 (formerly known as AZFb deletion), or 7.7 Mb between palindromes P5 and distal P1 (formerly, deletion AZFb plus AZFc) [Repping et al 2002]. Another less common deletion removes 7 Mb between palindromes P4 and distal P1. Smaller deletions within AZFc that involve palindromes gr/gr, b1/b3, or b2/b3 are generally considered benign but may be associated with infertility in certain ethnic groups (Figure 1) [Stouffs et al 2011]. Partial deletion in AZFb that removes the entire P4 palindrome apparently decreases spermatocyte maturation but can be transmitted [Kichine et al 2012].

A subset of Y deletions appear to be terminal by cytogenetic and PCR analyses. Such deletions, often associated with severely impaired spermatogenesis, remove either all or part of the AZF regions along with the terminal q12 band of the Y chromosome, depending on the breakpoints. These so-called “terminal deletions” are usually not terminal, but rather can represent more complex rearrangements such as isodicentric Y chromosomes, which are often unstable and associated with a mosaic 45,X cell line. In fact, Turner syndrome (45,X) can be caused by the loss of an isodicentric Y chromosome [Lange et al 2009].

Y chromosome deletions can be associated with defects in the pseudoautosomal regions (PAR), resulting in copy number changes in PAR genes such as SHOX, a gene important for stature [Jorgez et al 2011]. These aberrations are prevalent in complex rearrangements of the Y chromosome, and can often be detected by CMA analyses.

So far, only one single copy gene, USP9Y, has been implicated in the infertility phenotype by the finding of gene-limited mutations in two individuals [Sun et al 1999]. However, complete deletion of this gene can be associated with mild hypospermatogenesis and fertility [Luddi et al 2009]. Note that many Y-linked genes are multi-copy and thus interpretation of mutations is difficult.

Normal allelic variants. The normal Y chromosome contains all AZF regions. A complete sequence analysis of the Y chromosome and a listing of Y-linked genes have been reported [Skaletsky et al 2003; Silber 2011; Hughes & Rozen 2012; Rozen et al, in press]. Most genes located in the AZF regions on the Y chromosome are specifically and only expressed in testis and are candidates for a role in male fertility. Other still uncharacterized transcripts could also play a role in male fertility. USP9Y is the only single-copy gene directly implicated in male fertility by virtue of a mutation found in an infertile male [Sun et al 1999].

The reader is referred to the NCBI Web site for current annotation of Y-linked genes. Below is a short description of some of the genes that are thought to play a role in male fertility. The role of these genes in the disorder is still putative and derives from the gene location, its expression in germ cells, and/or homology to genes involved in fertility in other species. It should be noted that several of the Y-linked genes are present in multiple copies on the Y chromosome; the presence of multiple copies complicates the unraveling of their roles in male fertility.

  • USP9Y is a single-copy gene located in the proximal AZFa region. USP9Y and its X-linked paralogue USP9X encode proteins similar to ubiquitin-specific proteases. USP9Y-limited alterations in two infertile males have directly implicated this gene in male fertility [Sun et al 1999]. However, complete deletion of this gene can be associated with mild hypospermatogenesis and fertility [Luddi et al 2009].
  • DDX3Y is a single-copy gene located in AZFa that has a paralogue on the X chromosome, DDX3. These genes encode DEAD box proteins and are ubiquitously expressed, but DDX3Y produces an alternative transcript in testis [Lahn & Page 1997]. Translation of DDX3Y is detected only in the male germ line, predominantly in spermatogonia [Ditton et al 2004].
  • VCY is a multi-copy gene family with paralogues on the X chromosome (VCX, VCX2). VCY (BPY1) and BPY2 (VCY2) located in AZFb/c are expressed in male germ cells, with BPY2 specifically expressed in spermatogonia, spermatocytes, and round spermatids [Lahn & Page 2000, Tse et al 2003].
  • HSFY1 and HSFY2 in AZFb and their X paralogue HSFX1 are members of the family of heat shock transcription factors. HSFY1 and HSFY2 expression is restricted to Sertoli cells and spermatogenic cells [Shinka et al 2004, Vinci et al 2005]. HSFY1 and HSFY2 deletions contribute to a slight reduction in spermatocyte maturation [Kichine et al 2012].
  • KDM5D is a single-copy gene located in AZFb with a paralogue KDM5C on the X chromosome. This gene encodes for a histone demethylase specifically implicated in male meiosis [Akimoto et al 2008].
  • RPS4Y2 located in AZFb encodes a ribosomal protein specifically expressed in testis. In contrast, the Y-linked RPS4Y1 (located in the short arm of the Y) and the X-linked RPS4X paralogues are ubiquitously expressed [Lopes et al 2010].
  • RBMY is a multi-copy gene family located in AZFb and in other regions on the short and long arms of the Y chromosome. There are about 15-20 copies of RBMY, but only six appear functional. An X-linked paralogue, RBMX is ubiquitously expressed [Delbridge et al 1999]. RBMY genes are expressed only in testis and produce proteins that bind to RNA and modulate the activity of splicing factors [Skrisovska et al 2007, Dreumont et al 2010].
  • PRY is a multi-copy gene family with four members. PRY1/2 are located in AZFb and PRY3/4, in AZFc. These genes encode proteins with a low degree of similarity to protein tyrosine phosphatase, non-receptor type 13, which may be involved in apoptosis of damaged spermatids and spermatozoa [Stouffs et al 2004].
  • DAZ is a multi-copy gene family located in AZFc. The DAZ gene family is organized in a repeat cluster containing four copies (DAZ1-4) [Saxena et al 2000]. The DAZ genes have a paralogue on human chromosome 3 (DAZL). They encode for RNA-binding proteins expressed in spermatogonia and implicated in development of haploid gametes [Menke et al 1997, Kee et al 2009].
  • CDY is a multi-copy gene family, with four apparently functional copies (CDY1, CDY1B, CDY2A and CDY2B) located in AZFb/c. CDY genes represent processed transposons from an autosomal gene (CDYL) that has been amplified on the Y chromosome in the simian lineage. CDY genes encode for chromodomain proteins specifically expressed in mature spermatids where they may facilitate the histone to protamine transition [Lahn et al 2002, Dorus et al 2003].

Pathologic allelic variants. The abnormality of the Y chromosome associated with male infertility results in deletion of genes. The Y chromosome deletions are usually very large and thus result in deletion of multiple genes. Several regions of the Y chromosome long arm have been implicated (Figure 1).

Note: In addition to single-gene entries OMIM lists two Y deletion syndromes:

  • 400042 SPERMATOGENIC FAILURE, Y-LINKED, 1 (SPGFY1), which corresponds to AZFa deletion syndrome associated with SCOS, and
  • 415000 SPERMATOGENIC FAILURE, Y-LINKED, 2 (SPGFY2), which refers to AZFa, b, or c.

See Table B.

Normal gene product. Several genes are included in the AZF regions deleted in males with infertility. However, as discussed above, their role in normal spermatogenesis is not fully known. Refer to NCBI for a current list of Y-linked genes and their annotation in terms of protein product.

Abnormal gene product. The Y chromosome deletions result in absence of gene products. The deletions often comprise more than one gene or multiple copies of the gene. In the case of USP9Y, a deletion limited to the gene was found as well as one mutation (4-bp deletion) that results in skipping of an exon and protein truncation [Sun et al 2000].

References

Published Guidelines/Policy Statements

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Literature Cited

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Suggested Reading

  1. Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, Krausz C. EAU Working Group on Male Infertility; European Association of Urology guidelines on Male Infertility: the 2012 update. Eur Urol. 2012;62(2):324–32. [PubMed: 22591628]
  2. Krausz C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011;25(2):271–85. [PubMed: 21397198]
  3. Massart A, Lissens W, Tournaye H, Stouffs K. Genetic causes of spermatogenic failure. Asian J Androl. 2012;14:40–8. [PMC free article: PMC3735159] [PubMed: 22138898]

Chapter Notes

Revision History

  • 18 October 2012 (me) Comprehensive update posted live
  • 19 March 2007 (me) Comprehensive update posted to live Web site
  • 28 February 2006 (cmd) Revision: Diagnosis: Cytogenetic analysis
  • 16 September 2004 (me) Comprehensive update posted to live Web site
  • 6 February 2004 (cd) Revision: change in gene name
  • 31 October 2002 (me) Review posted to live Web site
  • January 2001 (cmd) Original submission
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