Clinical Diagnosis

Males with Y chromosome infertility usually have a normal physical examination, although some have small testes and/or cryptorchidism. Of note, some males may have both a Y chromosome abnormality and varicocele, which by itself can cause infertility.

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

Semen analysis. Ejaculate is examined to determine the number, motility, and morphology of sperm. The following categories of sperm count are identified (Table 1):

Testing

Cytogenetic analysis. Approximately 5%-10% of men with unexplained infertility associated with azoospermia/oligozoospermia and/or abnormalities of sperm morphology/motility have chromosome abnormalities, mostly gonosomal (i.e., involving the sex chromosomes) but also autosomal.

Routine cytogenetic studies 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.

• Other more complex Y chromosome rearrangements that lead to long arm deletions. For example, a pseudodicentric Y chromosome (also called "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 of them (pseudodicentric Y chromosomes and ring Y chromosomes) are often associated with a 45,X cell line.

However, cytogenetic analysis alone cannot:

• Detect microdeletions of the Y chromosome

• Determine whether a cytogenetically visible deletion extends into the AZF regions

• Detect small interstitial deletions in 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 germ cells

• Hypospermatogenesis associated with reduced number of germ cells or arrest of germ cells at different developmental stages

Molecular Genetic Testing

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

• Microdeletions 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 in USP9Y

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, HSFY1, RBMY, CDY1, and DAZ) located along the Y chromosome should be included in the analysis to assess Y chromosome integrity.
  
  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 insufficient, especially in 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 are thought to be non-overlapping. However, subsequent studies showed that AZFB and AZFC overlap [Repping et al 2002] (see Figure 1). 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].

Research testing

• Single gene defects. 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 usually not detectable by PCR analyses and thus require other types of testing (e.g., sequence analysis) that are presently done on a research basis only.

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

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Test Method	Genetic Mechanism	Phenotype	Mutation Detection Frequency 1	Test Availability
Deletion / duplication analysis	Interstitial AZFA deletion (HERV15yq1-HERV15yq2) 2	SCOS	9%	Clinical
	Interstitial AZFC deletion (b2/b4) 2	Oligozoospermia	6%
		Azoospermia	13%
	Intermediate AZFB and AZFB+C deletions (P5/proxP1, P5/distP1, P4/distP1) 2	Azoospermia	1%-2%
	Terminal AZF	ND	ND

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

SCOS = Sertoli-cell-only syndrome

ND = No data

1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method

2. 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]

Testing Strategy

Sperm counts and morphology/motility should be assessed and routine cytogenetic analysis performed together with molecular genetic testing for microdeletions of the long arm of the Y chromosome.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No disorders other than infertility are known to be caused by deletions of the long arm of the Y chromosome in the AZF regions. Men with Y chromosome deletions and infertility are otherwise healthy.

A single study suggested that one of the deletions of the Y chromosome in AZFC region (designated gr/gr) also causes a slight increase in susceptibility to testicular germ cell tumors [Nathanson et al 2005].

Natural History

Males with Y chromosome infertility usually have no obvious symptoms, although physical examination may reveal small testes and/or cryptorchidism. Males with Y chromosome infertility have azoospermia or severe, moderate, or mild oligozoospermia (Table 1). Mild oligozoospermia may be compatible with fertility in rare 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].

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.

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 author includes reference to these regions and to the palindromic repeats that now define the deletions more precisely.

• Interstitial or terminal deletions that include AZFA, often mediated by recombination between the HERV15yq1-HERV15yq2 repeats, usually produce the severe phenotype of Sertoli-cell-only syndrome (SCOS) [Kamp et al 2001].

• 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 usually result in azoospermia [Repping et al 2002].

• Interstitial or terminal deletions that include AZFC only are mediated by recombination between the b2/b4 palindromic repeats and result in a variable phenotype, ranging from azoospermia and SCOS to severe or mild oligozoospermia [Oates et al 2002]. This type of deletion can occasionally be associated with normal fertility in younger males, with the phenotype worsening with age [Chang et al 1999, Saut et al 2000].

• Two partial deletions of AZFC, called b1/b3 and gr/gr, are considered polymorphisms [Repping et al 2003, Fernandes et al 2004, Machev et al 2004, Ferlin et al 2007].

• Duplication of the AZFA region has been reported and does not appear to be associated with an abnormal phenotype [Bosch & Jobling 2003].

• So far, only one 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]. This study suggests that the SCOS phenotype usually associated with AZFA deletion is not caused by USP9Y deletion alone but must include deletion of at least one other gene, DDX3Y, to result in the severe phenotype. These findings underscore the complexity of the AZF region, which contains multiple genes, each of which is present in multiple copies.

Penetrance

Rarely within a family, the same deletion of the Y chromosome can cause infertility in some males but not others [Chang et al 1999, Saut et al 2000, Gatta et al 2002, Repping et al 2003]; hence, some fertile males with deletion of the AZF regions have fathered sons who are infertile.

Prevalence

The prevalence of Y chromosome deletions and microdeletions is estimated to be about 1:2000 to 1:3000 males.

The frequency of Yq microdeletions in males with azoospermia or severe oligozoospermia is about 5%-10% [Vogt 1997, Silber et al 1998, Oates et al 2002]. Some reports indicate that males with azoospermia apparently caused by other factors, such as hypogonadotropic hypogonadism, varicocele, or infection, may also have an increased incidence of Yq deletions [Krausz et al 1999].

Differences in prevalence based on ethnicity have not been observed.

Evaluations Following Initial Diagnosis

In an individual diagnosed with Y chromosome infertility, semen analysis to determine the number, motility, and morphology of sperm is appropriate.

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). 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 males with deletions of AZFC, and rarely for males with deletions of AZFB or AZFA. This procedure should not be performed in males with SCOS, in which no sperm are present [Krausz et al 2000, Stouffs et al 2005, Reyes-Vallejo et al 2006].

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 the fertilization or pregnancy rates [Oates et al 2002, Kihaile et al 2004]. The risk for birth defects is not increased in children conceived in this manner [Choi et al 2004].

Males with SCOS do not have germ cells in their testes; thus, testicular sperm extraction is not an option.

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 SCOS, usually associated with AZFB and AZFA deletions, but has been achieved for males with AZFC deletions [Krausz et al 1999, Stouffs et al 2005, Reyes-Vallejo et al 2006].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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.

• Rarely within a family, the same deletion of the Y chromosome can cause infertility in some individuals but not others [Chang et al 1999, Saut et al 2000, Gatta et al 2002, Repping et al 2003]; hence, some fertile males with deletion of the AZF regions have fathered sons who are infertile.

• Theoretically, a father could be mosaic for the deletion of the AZF regions; however, this situation has not yet been reported.

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 low. On rare occasions, however, the brothers of a proband may be at risk because within a family the same deletion of the AZF regions can result in infertility in some individuals but not in others [Chang et al 1999, Saut et al 2000, Repping et al 2003].

Offspring of a proband

• Pregnancies have been achieved from males with infertility caused by deletion of the AZF regions using intracytoplasmic sperm injection (ICSI).

• Male fetuses have the same deletion as their father, with a high risk of male infertility [Page et al 1999, Oates et al 2002]. However, if germ cell mosaicism were present in the infertile male undergoing ICSI (no such individual has been reported to date), some of his sons may not have the deletion.

• Female fetuses from a father with a Y chromosome deletion have no increased risk of congenital abnormalities or infertility.

Other family members. It is unlikely that extended family members are at increased risk for Y chromosome infertility. However, because AZF deletions can be expressed differently in family members, male relatives (e.g., a proband's paternal uncles and their sons) may be at risk.

Related Genetic Counseling Issues

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. See for a list of laboratories offering DNA banking.

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 about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Testing includes determining the sex of the fetus and/or the presence of a Y chromosome deletion. Prenatal diagnosis is also available for pregnancies at risk for chromosome abnormalities (such as 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 available for pregnancies conceived through assisted reproductive technology (ART) and at risk of resulting in a male with Y chromosome deletion. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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.

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]. 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. Specific genes are included in the AZF regions. USP9Y and DDX3Y are located in AZFA. HSFY1, XKRY, RBMY1A1, DAZ, JARID1D, EIF1AY, RPS4Y2, PRY, CDY1, CDY2, BPY2, CsSPG4LY, GOLGA2LY, and eight TTTY transcripts are located in AZFB and C.

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 [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. 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]. Additional deletions, for example a 7-Mb deletion between palindromes P4 and distal P1, have been described but are less common.

Some Y deletions appear to be terminal by cytogenetic and PCR analyses. These deletions remove either all or part of the AZF regions along with the terminal q12 band of the Y chromosome, depending on the breakpoints. They may be associated with pseudodicentric or ring Y chromosomes.

Specific genes within the deletions have been mapped. However, so far only one gene (USP9Y) has been implicated in the infertility phenotype by the finding of gene-limited mutations in two individuals [Sun et al 1999].

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]. All genes located in the AZF regions on the Y chromosome and specifically expressed in testis (e.g., RBMY1A1, DAZ, VCY, XKRY, CDY1, CDY2, HSFY1, PRY, BPY2) are candidates for a role in male fertility, though their exact function may be presently unknown. Genes that are ubiquitously expressed or expressed in more than one tissue (e.g., RPS4Y2, USP9Y, DDX3Y, UTY, JARID1D, EIF1AY) and other still uncharacterized transcripts could also play a role in male fertility. USP9Y is the only gene that has been directly implicated in male fertility, based on the finding of gene alterations in two infertile males [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 (also called DFFRY) is a single-copy gene located in the proximal AZFA region [Brown et al 1998]. USP9Y has a homologue on the X chromosome, USP9X (also called DFFRX). Both X and Y genes are ubiquitously expressed. These genes are homologous to the Drosophila melanogaster gene faf (fat facets) that plays a role in eye development and in female germ cell function. USP9Y-limited alterations in two infertile males have directly implicated this gene in male fertility [Sun et al 1999].

• DDX3Y (previously called DBY) is another single-copy gene located in AZFA that has a homologue on the X chromosome, DDX3 (previously called DBX). DDX3 and DDX3Y are ubiquitously expressed, but DDX3Y produces an alternative transcript in testis [Lahn & Page 1997].

• HSFY1 is a member of the family of heat shock transcription factors. Its expression is restricted to Sertoli cells and spermatogenic cells [Shinka et al 2004, Vinci et al 2005].

• RBMY (previously called YRRM) is a multi-copy gene family located in region AZFB and in other regions on the short and long arms of the Y chromosome. There are about 15-20 copies of RBMY. A homologue, RBMX (previously called HNRPG), is located on the X chromosome [Delbridge et al 1999]. RBMY2 is expressed only in testis.

• DAZ is a multi-copy gene family. The DAZ family on the human Y chromosome is organized in a repeat cluster containing four copies [Saxena et al 2000]. DAZ has a homologue on human chromosome 3 (DAZL). DAZ is homologous to bol in Drosophila melanogaster, in which mutations of bol cause meiotic arrest and azoospermia [Yen 2004, Reynolds & Cooke 2005]. Knock-out of Dazl in mouse results in azoospermia [Ruggiu et al 1997].

• CDY is a processed transposon from an autosomal gene that has been amplified on the Y chromosome in the simian lineage. CDY is specifically expressed in testis [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). One gene, USP9Y, has been directly implicated in male infertility. Two allelic variants represent mutations limited to USP9Y in two infertile males.

Note: OMIM lists one AZF locus, AZF1, which comprises AZFA, B, C, and SCOS.

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].

Published Guidelines/Consensus Statements

1. Male Infertility Best Practice Policy Committee of the American Urological Association; Practice Committee of the American Society for Reproductive Medicine. Report on evaluation of the azoospermic male. 2004. Available online. Accessed 1-19-12.

Literature Cited

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Suggested Reading

1. Krausz C. Y chromosome and male infertility: update, 2006. Front Biosci. 2006;11:3049–61. [PubMed: 16720375]
2. McElreavey K, Ravel C, Chantot-Bastaraud S, Siffroi JP. Y chromosome variants and male reproductive function. Int J Androl. 2006;29:298–303. [PubMed: 16466551]
3. Yen PH. Putative biological functions of the DAZ family. Int J Androl. 2004;27:125–9. [PubMed: 15139965]

Revision History

• 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