Clinical 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 established in a male with characteristic clinical and laboratory features and by identification of a hemizygous deletion of Yq involving the AZF regions or identification of a heterozygous pathogenic variant involving USP9Y (located within AZFa).

Management.

Treatment of manifestations: Pregnancies may be achieved by in vitro fertilization using intracytoplasmic sperm injection (ICSI), 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 that 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.

Suggestive Findings

Y chromosome infertility should be suspected in males with the following clinical and laboratory features.

Clinical features

• A history of infertility
• Normal physical examination in ~30%
• Small testes in ~70% (males with Sertoli cell-only syndrome)

Laboratory features

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).

Testicular biopsy. Testicular biopsy may reveal either one or a combination of the following:

• Sertoli cell-only (SCO) syndrome, 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

Establishing the Diagnosis

The diagnosis of Y chromosome infertility is established in a male with characteristic clinical and laboratory features and one of the following identified on molecular genetic testing (see Table 2):

• A hemizygous deletion of Yq involving the AZF regions (see Figure 1) (~99% of affected individuals) [Colaco & Modi 2018]
• A heterozygous USP9Y pathogenic (or likely pathogenic) variant in the AZFa region (1% of affected individuals) [Silber 2011]

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 Establishing the Diagnosis). (more...)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous USP9Y variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of Tier 1 testing (targeted deletion/duplication analysis or chromosomal microarray analysis) and Tier 2 testing (cytogenetic analysis and single-gene testing).

Clinical Description

Males with Y chromosome infertility usually have no symptoms other than infertility. A physical examination may reveal small testes in those with Sertoli cell-only (SCO) syndrome. Physical examination is normal in approximately 30% of males with Y chromosome infertility.

Males with Y chromosome infertility have azoospermia or severe, moderate, or mild oligozoospermia depending on the location and size of the Y chromosome deletion (see Genotype-Phenotype Correlations). Most males with AZFa or AZFb/c deletions have a very poor prognosis for finding any sperm with testicular sperm extraction (TESE). Males with AZFc deletions (b2/b4 or gr/gr) have an extremely favorable prognosis (87%) for finding sperm sufficient for successful intracytoplasmic sperm injection (ICSI).

Oligozoospermia may be compatible with fertility when the female partner is very fertile.

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 multicopy 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 result in the severe phenotype of Sertoli cell-only (SCO) syndrome [Silber 2011] (see Differential Diagnosis). The interstitial deletions are mediated by recombination between the HERV15yq1 and HERV15yq2 repeats. One single-copy gene (USP9Y) located in AZFa has been directly implicated in the infertility phenotype, following detection of a single-nucleotide variant and a deletion limited to this gene in two infertile males with hypospermatogenesis but without SCO syndrome [Sun et al 1999]. Complete deletion of USP9Y has been found in fertile individuals, albeit with hypospermatogenesis [Luddi et al 2009], suggesting that SCO syndrome 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 due to mature arrest [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 SCO syndrome to severe oligozoospermia [Oates et al 2002, Silber 2011]. This type of deletion is common. Eighty-seven percent of males with this deletion will have some spermatozoa either in the ejaculate or at testicular sperm extraction that can lead to successful intracytoplasmic sperm injection [Silber 2011].
• Two partial deletions of AZFc, called b1/b3, b2/b3, are considered benign copy number variants (polymorphisms) [Repping et al 2003, Fernandes et al 2004, Machev et al 2004, Ferlin et al 2007].
• Another partial deletion of AZFc, 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]. The gr/gr deletion removes two of the four copies of DAZ in the AZFc region, and is a risk factor for oligospermia. The role of DAZ in spermatogenesis is quantitative. Usually the loss of all four copies of DAZ does not prevent some spermatogenesis from occurring because of the compensatory function of DAZL on chromosome 3.
• 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 [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 1:2,000 to 1:3,000 males [de Vries et al 2002; de Vries et al, personal communication].

The frequency of Yq microdeletions in males with azoospermia or severe oligozoospermia is about 5% [Kim et al 2017].

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]. The gr/gr deletion is extremely common (25%) in Japanese men, for example, and represents simply a "risk factor" for male infertility.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Y chromosome infertility, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Semen analysis to determine the number, motility, and morphology of sperm
• Consultation with a clinical geneticist and/or genetic counselor

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 by ICSI into a harvested egg by IVF (in vitro fertilization) [Silber et al 1998].

Retrieval of sperm has been successful for most males with deletions of AZFc, but 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 "backup 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 "backup" copies for genes in AZFa and AZFb.

The definition of Sertoli cell-only (SCO) 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 individuals, a few spermatocytes do progress to sperm and can be retrieved from the testis. Similarly, in about 60% of males with SCO syndrome 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 [Silber 2011]. The risk for birth defects is not different from that of any infertile couple that achieves a pregnancy through assisted reproductive technology [Davies et al 2012].

Agents/Circumstances to Avoid

Hormones or nutritional supplements could reduce severe oligospermia to complete azoospermia [Hughes & Page 2015].

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Ongoing studies are evaluating the use of skin biopsy in azoospermic men to make induced pluripotent stem cells (iPSC) differentiate into primordial germ cells and ultimately sperm [Author, personal communication].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

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 [Silber 2011].

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 typically infertile, the deletions are usually de novo and therefore not present in the father of the proband (except for gr/gr; see below).
• Rarely, a male with an AZFc deletion of the Y chromosome has fathered a son, who is infertile [Faddy et al 2001, Silber & Repping 2002]. 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].
  The gr/gr deletion is a "partial AZFc deletion" of only two of the four copies of DAZ; gene dosage therefore affects the severity of the defect in spermatogenesis [de Vries et al 2002] (see Genotype-Phenotype Correlations).
• Deletions of b1/b3 and b2/b3 are inconsequential, and have no effect on male fertility.
• Note: Using ICSI-IVF (see Treatment of Manifestations), most azoospermic men can conceive children despite the most severe spermatogenic defect; male offspring will inherit the same AZFc deletion as their azoospermic father [Silber 2011].

Sibs/brothers of a proband

• Because most Y chromosome deletions found in an infertile male are de novo, the risk to the brothers of a proband is very low. However, if the proband has a gr/gr deletion, risk to the brothers of a proband is increased, as there is a higher likelihood that their father also has a gr/gr deletion.
• 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 that all men with the AZFc deletion have a severe spermatogenic defect, which is only rarely compensated for by high fertility in their partner.

Offspring of a proband

• Pregnancies have been achieved from males with infertility caused by Y chromosome deletion using ICSI.
• Male fetuses have the same Y chromosome deletion as their father, with a high risk for male infertility. The deletion is not amplified or corrected in subsequent generations [Oates et al 2002].
• Female fetuses from a father with a Y chromosome deletion are not at increased risk for congenital abnormalities or infertility [Silber et al 1998, Silber & Repping 2002].

Other family members. It is unlikely that extended family members are at increased risk for Y chromosome infertility since Y chromosome deletions are almost always de novo events that occur in 1/2,000 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. It is appropriate to inform men with non-obstructive azoospermia or severe oligospermia who undergo TESE-ICSI (testicular sperm extraction – intracytoplasmic sperm injection) that their condition is likely genetic and could be due to a Y chromosome deletion, translocation, or Klinefelter syndrome (47, XXY). (Note: Most men with Klinefelter syndrome appear clinically asymptomatic.)

Prenatal Testing and Preimplantation Genetic Testing

Once the causative genetic alteration has been identified in a male with Y chromosome infertility, prenatal testing for pregnancies conceived through assisted reproductive technology (ART) and at risk of resulting in a male with Y chromosome deletion is possible. Testing includes determining the sex of the fetus and/or the presence of a Y chromosome deletion.

Prenatal testing 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), although such Y chromosome alterations would rarely be associated with residual spermatogenesis.

Preimplantation genetic testing may be an option for some pregnancies conceived through ART and at risk of resulting in a male with Y chromosome deletion.

Molecular Pathogenesis

Introduction. Three azoospermia regions on the Y chromosome have been defined as AZFa, AZFb, and AZFc. The normal Y chromosome contains all AZF regions. Most genes located in the AZF regions on the Y chromosome are specifically expressed in testis and are candidates for a role in male fertility. Other, still uncharacterized transcripts could also play a role in male fertility. Note that many Y-linked genes are multicopy and thus interpretation of sequence variants is difficult. Pathogenic variants in two single-copy genes, USP9Y and DDX3Y, cause Y chromosome infertility:

• USP9Y is a single-copy gene located in the proximal AZFa region. USP9Y and its X-linked paralog USP9X encode proteins similar to ubiquitin-specific proteases. Deletion of USP9Y is associated with mild hypospermatogenesis and fertility [Luddi et al 2009].
• DDX3Y is a single-copy gene located in AZFa that has a paralog 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 germline, predominantly in spermatogonia [Ditton et al 2004].

Other Y chromosome genes, such as VCY, KDM5D, RPS4Y2, PRY, DAZ, and CDY, may 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.

Mechanism of disease causation. Massive interstitial Y chromosome deletions associated with male infertility are mediated by recombination between palindromic repeats on the Y chromosome. The regions have been defined on the basis of deletion intervals found in infertile males.

AZFa:

• 792 kb long and just distal to the centromere
• Recombination between two HERV15 (HERV15yq1-HERV15yq2) proviral sequences [Kamp et al 2000, Sun et al 2000, Kamp et al 2001]

AZFb and AZFc:

• Just proximal to the Yq12 heterochromatic band
• The most common Y chromosome deletion removes 3.5 Mb between palindromes b2 and b4 [Kuroda-Kawaguchi et al 2001, Vogt 2005].
• Recurrent deletions:
  • 6.2 Mb (AZFb/c) between palindromes P5 and proximal P1
  • 7.7 Mb between palindromes P5 and distal P1
  • 7 Mb between palindromes P4 and distal P1
• Smaller deletions (AZFb) between palindromes gr/gr, b1/b3, or b2/b3 are generally considered benign but may be associated with infertility in certain ethnic groups [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].

Y chromosome infertility due to pathogenic variants in USP9Y or DDX3Y occurs through a loss-of-function mechanism.

Laboratory considerations for Y chromosome infertility: nomenclature. Sequencing of AZFc and of the complete Y chromosome has more accurately depicted the Y deletions. For example, AZFc is referred to as b2/b4. AZFb overlaps AZFc and is referred to more accurately as P5/proximal p1. AZFb+c deletions are p5 or p4 distal p1. Nonetheless, the most commonly used (though less accurate) nomenclature is still AZFa,b,+c.

Author Notes

Infertility Center of St. Louis
St Luke's Hospital
St Louis Missouri

Whitehead Institute
Massachusetts Institute of Technology
Cambridge, Massachusetts

American Society for Reproductive Medicine
Birmingham, Alabama
Telephone: (205) 978-5000
Fax: (205) 978-5005
asrm@asrm.org

Author History

Christine M Disteche, PhD; University of Washington (2002-2019)
Yuting Fan, MD (2019-present)
Sherman J Silber, MD (2012-present)

Revision History

• 1 August 2019 (sw) Comprehensive update posted live
• 18 October 2012 (me) Comprehensive update posted live
• 19 March 2007 (me) Comprehensive update posted live
• 28 February 2006 (cmd) Revision: Diagnosis: Cytogenetic analysis
• 16 September 2004 (me) Comprehensive update posted live
• 6 February 2004 (cd) Revision: change in gene name
• 31 October 2002 (me) Review posted live
• January 2001 (cmd) Original submission

Published Guidelines / Policy Statements

• CUA Guideline: The workup and management of azoospermic males. Canadian Urological Association. Available online. 2015. Accessed 4-18-23.
• Evaluation of the azoospermic male: a committee opinion. Practice Committee of the American Society for Reproductive Medicine in collaboration with the Society for Male Reproduction and Urology. Available online. 2018. Accessed 4-18-23.

Literature Cited

• Bosch E, Jobling MA. Duplications of the AZFa region of the human Y chromosome are mediated by homologous recombination between HERVs and are compatible with male fertility. Hum Mol Genet. 2003;12:341–7. [PubMed: 12554687]
• Chang PL, Sauer MV, Brown S. Y chromosome microdeletion in a father and his four infertile sons. Hum Reprod. 1999;14:2689–94. [PubMed: 10548602]
• Chillón M, Casals T, Mercier B, Bassas L, Lissens W, Silber S, Romey MC, Ruiz-Romero J, Verlingue C, Claustres M, Nunes V, Férec C, Estivill X. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995;332:1475–80. [PubMed: 7739684]
• Colaco S, Modi D. Genetics of the human Y chromosome and its association with male infertility. Reprod Biol Endocrinol. 2018;16:14. [PMC free article: PMC5816366] [PubMed: 29454353]
• Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, Haan EA, Chan A. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366:1803–13. [PubMed: 22559061]
• de Vries JW, Repping S, van Daalen SK, Korver CM, Leschot NJ, van der Veen F. Clinical relevance of partial AZFc deletions. Fertil Steril. 2002;78:1209–14. [PubMed: 12477514]
• Ditton HJ, Zimmer J, Kamp C, Rajpert-De Meyts E, Vogt PH. The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum Mol Genet. 2004;13:2333–41. [PubMed: 15294876]
• Faddy MJ, Silber SJ, Gosden RG. Intra-cytoplasmic sperm injection and infertility. Nat Genet. 2001;29:131. [PubMed: 11586293]
• Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, Lenzi A, Foresta C. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab. 2007;92:762–70. [PubMed: 17213277]
• Fernandes S, Paracchini S, Meyer LH, Floridia G, Tyler-Smith C, Vogt PH. A large AZFc deletion removes DAZ3/DAZ4 and nearby genes from men in Y haplogroup N. Am J Hum Genet. 2004;74:180–7. [PMC free article: PMC1181906] [PubMed: 14639527]
• Giachini C, Laface I, Guarducci E, Balercia G, Forti G, Krausz C. Partial AZFc deletions and duplications: clinical correlates in the Italian population. Hum Genet. 2008;124:399–410. [PubMed: 18807255]
• Hughes JF, Page DC. The biology and evolution of mammalian Y chromosomes. Annu Rev Genet. 2015;49:507–27. [PubMed: 26442847]
• Jorgez CJ, Weedin JW, Sahin A, Tannour-Louet M, Han S, Bournat JC, Mielnik A, Cheung SW, Nangia AK, Schlegel PN, Lipshultz LI, Lamb DJ. Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions. J Clin Endocrinol Metab. 2011;96:E674–9. [PMC free article: PMC3070254] [PubMed: 21252244]
• Kamp C, Hirschmann P, Voss H, Huellen K, Vogt PH. Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events. Hum Mol Genet. 2000;9:2563–72. [PubMed: 11030762]
• Kamp C, Huellen K, Fernandes S, Sousa M, Schlegel PN, Mielnik A, Kleiman S, Yavetz H, Krause W, Küpker W, Johannisson R, Schulze W, Weidner W, Barros A, Vogt PH. High deletion frequency of the complete AZFa sequence in men with Sertoli-cell-only syndrome. Mol Hum Reprod. 2001;7:987–94. [PubMed: 11574668]
• Katsumi M, Ishikawa H, Tanaka Y, Saito K, Kobori Y, Okada H, Saito H, Nakabayashi K, Matsubara Y, Ogata T, Fukami M, Miyado M. Microhomology-mediated microduplication in the y chromosomal azoospermia factor a region in a male with mild asthenozoospermia. Cytogenet Genome Res. 2014;144:285–9. [PubMed: 25765000]
• Kichine E, Rozé V, Di Cristofaro J, Taulier D, Navarro A, Streichemberger E, Decarpentrie F, Metzler-Guillemain C, Lévy N, Chiaroni J, Paquis-Flucklinger V, Fellmann F, Mitchell MJ. HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation. Hum Reprod. 2012;27:615–24. [PubMed: 22158087]
• Kim SY, Kim HJ, Lee BY, Park SY, Lee HS, Seo JT. Y chromosome microdeletions in infertile men with non-obstructive azoospermia and severe oligozoospermia. J Reprod Infertil. 2017;18:307–15. [PMC free article: PMC5641440] [PubMed: 29062795]
• Kirsch S, Weiss B, Schön K, Rappold GA. The definition of the Y chromosome growth-control gene (GCY) critical region: relevance of terminal and interstitial deletions. J Pediatr Endocrinol Metab. 2002;15 Suppl 5:1295–300. [PubMed: 12510983]
• Kirsch S, Weiss B, Zumbach K, Rappold G. Molecular and evolutionary analysis of the growth-controlling region on the human Y chromosome. Hum Genet. 2004;114:173–81. [PubMed: 14579146]
• Kuroda-Kawaguchi T, Skaletsky H, Brown LG, Minx PJ, Cordum HS, Waterston RH, Wilson RK, Silber S, Oates R, Rozen S, Page DC. The AZFc region of the Y chromosome features massive palindromes and uniform recurrent deletions in infertile men. Nat Genet. 2001;29:279–86. [PubMed: 11687796]
• Lahn BT, Page DC. Functional coherence of the human Y chromosome. Science. 1997;278:675–80. [PubMed: 9381176]
• Lange J, Skaletsky H, van Daalen SK, Embry SL, Korver CM, Brown LG, Oates RD, Silber S, Repping S, Page DC. Isodicentric Y chromosomes and sex disorders as byproducts of homologous recombination that maintains palindromes. Cell. 2009;138:855–69. [PMC free article: PMC3616640] [PubMed: 19737515]
• Luddi A, Margollicci M, Gambera L, Serafini F, Cioni M, De Leo V, Balestri P, Piomboni P. Spermatogenesis in a man with complete deletion of USP9Y. N Engl J Med. 2009;360:881–5. [PubMed: 19246359]
• Machev N, Saut N, Longepied G, Terriou P, Navarro A, Levy N, Guichaoua M, Metzler-Guillemain C, Collignon P, Frances AM, Belougne J, Clemente E, Chiaroni J, Chevillard C, Durand C, Ducourneau A, Pech N, McElreavey K, Mattei MG, Mitchell MJ. Sequence family variant loss from the AZFc interval of the human Y chromosome, but not gene copy loss, is strongly associated with male infertility. J Med Genet. 2004;41:814–25. [PMC free article: PMC1735624] [PubMed: 15520406]
• Noordam MJ, Westerveld GH, Hovingh SE, van Daalen SK, Korver CM, van der Veen F, van Pelt AM, Repping S. Gene copy number reduction in the azoospermia factor c (AZFc) region and its effect on total motile sperm count. Hum Mol Genet. 2011;20:2457–63. [PubMed: 21429917]
• Oates RD, Silber S, Brown LG, Page DC. Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI. Hum Reprod. 2002;17:2813–24. [PubMed: 12407032]
• Practice Committee of the American Society for Reproductive Medicine. Report on evaluation of the azoospermic male. Fertil Steril. 2004;82 Suppl 1:S131–6. [PubMed: 15363709]
• Repping S, Skaletsky H, Brown L, van Daalen SK, Korver CM, Pyntikova T, Kuroda-Kawaguchi T, de Vries JW, Oates RD, Silber S, van der Veen F, Page DC, Rozen S. Polymorphism for a 1.6-Mb deletion of the human Y chromosome persists through balance between recurrent mutation and haploid selection. Nat Genet. 2003;35:247–51. [PubMed: 14528305]
• Repping S, Skaletsky H, Lange J, Silber S, Van Der Veen F, Oates RD, Page DC, Rozen S. Recombination between palindromes P5 and P1 on the human Y chromosome causes massive deletions and spermatogenic failure. Am J Hum Genet. 2002;71:906–22. [PMC free article: PMC419997] [PubMed: 12297986]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Saut N, Terriou P, Navarro A, Levy N, Mitchell MJ. The human Y chromosome genes BPY2, CDY1 and DAZ are not essential for sustained fertility. Mol Hum Reprod. 2000;6:789–93. [PubMed: 10956550]
• Silber SJ. The varicocele dilemma. Hum Reprod Update. 2001;7:70–7. [PubMed: 11212078]
• Silber SJ. The Y chromosome in the era of intracytoplasmic sperm injection: a personal review. Fertil Steril. 2011;95:2439-48.e1-5. [PubMed: 21704208]
• Silber SJ, Alagappan R, Brown LG, Page DC. Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction. Hum Reprod. 1998;13:3332–7. [PubMed: 9886509]
• Silber SJ, Repping S. Transmission of male infertility to future generations: Lessons from the Y chromosome. Hum Reprod Update. 2002;8:217–29. [PubMed: 12078833]
• Stouffs K, Lissens W, Tournaye H, Haentjens P. What about gr/gr deletions and male infertility? Systematic review and meta-analysis. Hum Reprod Update. 2011;17:197–209. [PubMed: 20959348]
• Stouffs K, Lissens W, Tournaye H, Van Steirteghem A, Liebaers I. The choice and outcome of the fertility treatment of 38 couples in whom the male partner has a Yq microdeletion. Hum Reprod. 2005;20:1887–96. [PubMed: 15790609]
• Sun C, Skaletsky H, Birren B, Devon K, Tang Z, Silber S, Oates R, Page DC. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nat Genet. 1999;23:429–32. [PubMed: 10581029]
• Sun C, Skaletsky H, Rozen S, Gromoll J, Nieschlag E, Oates R, Page DC. Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses. Hum Mol Genet. 2000;9:2291–6. [PubMed: 11001932]
• Vogt PH. Azoospermia factor (AZF) in Yq11: towards a molecular understanding of its function for human male fertility and spermatogenesis. Reprod Biomed Online. 2005;10:81–93. [PubMed: 15705299]
• WHO. WHO Laboratory Manual for the Examination and Processing of Human Semen. 5 ed. Geneva, Switzerland: World Health Organization; 2010. Available online. Accessed 4-18-23.