Which genetic abnormalities are most commonly associated with male infertility?

The most common genetic abnormalities associated with male infertility include chromosomal abnormalities, Y chromosome microdeletions, and specific gene mutations that affect sperm production or the structure of the reproductive tract.

One of the most frequent conditions is Klinefelter syndrome (47,XXY), where a male has an extra X chromosome. This leads to reduced testosterone levels and impaired or absent sperm production, and it is a major cause of non-obstructive azoospermia (Kuroda et al., 2020).

Y chromosome microdeletions are another important cause. These involve missing sections of the Y chromosome, particularly in regions known as AZF (azoospermia factor), which are essential for sperm production. Depending on the extent of the deletion, this can result in severely reduced sperm counts or complete absence of sperm (Kuroda et al., 2020).

Structural chromosome abnormalities, such as balanced translocations (including Robertsonian and reciprocal translocations), are also commonly seen. Although individuals with these changes are usually healthy, the rearranged genetic material can disrupt normal sperm development and is associated with infertility and an increased risk of miscarriage (Kuroda et al., 2020).

In addition, mutations in the CFTR gene can lead to congenital bilateral absence of the vas deferens (CBAVD), a condition where the tubes that carry sperm are missing from birth. In these cases, sperm production is often normal, but sperm cannot be transported into the semen, resulting in obstructive infertility (Kuroda et al., 2020).

Overall, genetic abnormalities are an important underlying cause of male infertility, particularly in men with very low sperm counts or no sperm in the ejaculate.

Kuroda S, Usui K, Sanjo H, Takeshima T, Kawahara T, Uemura H, Yumura Y. Genetic disorders and male infertility. Reprod Med Biol. 2020;19(4):314–322. doi:10.1002/rmb2.12336.

How do Y chromosome microdeletions affect sperm production and fertility outcomes?

Y chromosome microdeletions affect male fertility by directly disrupting the genes that are essential for sperm production. These deletions occur in specific regions of the Y chromosome known as the azoospermia factor (AZF) regions (AZFa, AZFb, and AZFc), which contain genes that regulate different stages of spermatogenesis.

When these regions are partially or completely missing, sperm production can be severely reduced or completely absent. AZFa or AZFb deletions are typically associated with very poor fertility outcomes, including complete absence of sperm in the ejaculate (azoospermia), because they often lead to early failure of sperm cell development. In contrast, AZFc deletions may still allow limited sperm production, but counts are usually low and sperm quality is often reduced, meaning natural conception can be difficult but not always impossible.

These genetic changes also have a significant impact on assisted reproductive outcomes. Even when sperm can be retrieved using techniques such as testicular sperm extraction, studies show that fertilisation rates, embryo quality, and overall success of assisted reproduction may be reduced compared with men without these deletions. In addition, there is an important genetic counselling aspect, as Y chromosome microdeletions can be passed on to male offspring, meaning sons may inherit the same fertility issues.

Overall, Y chromosome microdeletions impair fertility by disrupting the genetic control of sperm development at different stages, with the severity of the impact depending on which region of the AZF locus is affected. Nasrin Pazoki et al. (2024) highlight that these deletions are strongly associated with impaired spermatogenesis, reduced sperm quality, and poorer outcomes in assisted reproductive techniques, particularly in men with severe oligozoospermia or azoospermia.

Pazoki N, Salehi M, Angaji SA, Abdollahpour-Alitappeh M. Elucidating the impact of Y chromosome microdeletions and altered gene expression on male fertility in assisted reproduction. Hum Mol Genet. 2024;33(17):1540–1553. https://doi.org/10.1093/hmg/ddae086

When should genetic testing be recommended for men experiencing infertility?

Genetic testing should not be performed in all men with infertility, but it is recommended in specific clinical situations where there is a higher likelihood of an underlying genetic cause.

Genetic testing is generally indicated in men with non-obstructive azoospermia (no sperm in the ejaculate due to impaired sperm production) or severe oligozoospermia (very low sperm count). These groups have the highest rates of chromosomal abnormalities and Y chromosome defects and therefore benefit most from targeted genetic evaluation (Pelzman & Hwang, 2021).

Testing is also recommended when there are additional clinical features suggestive of a genetic condition. These include findings such as testicular atrophy, elevated follicle-stimulating hormone (FSH), or suspected impaired spermatogenesis, as these may indicate an underlying chromosomal or genetic disorder affecting fertility (Pelzman & Hwang, 2021).

In addition, genetic testing is advised when there is suspicion of specific conditions that have known genetic causes. For example, men with suspected congenital absence of the vas deferens should be tested for CFTR gene mutations, as this is strongly associated with cystic fibrosis–related gene changes (Pelzman & Hwang, 2021).

Importantly, genetic testing is also recommended in cases of recurrent assisted reproductive failure or when there is concern about transmission of genetic abnormalities to offspring, as results can influence both prognosis and counselling for future reproductive options (Pelzman & Hwang, 2021).

Overall, genetic testing is most appropriate in men with severe abnormalities in semen parameters or clinical features suggestive of impaired sperm production, as it helps identify the underlying cause, guide treatment decisions, and inform reproductive counselling.

Pelzman DL, Hwang K. Genetic testing for men with infertility: techniques and indications. Transl Androl Urol. 2021 Mar;10(3):1354-1364. doi: 10.21037/tau-19-725. PMID: 33850771; PMCID: PMC8039607.

What is the relationship between cystic fibrosis gene mutations and male reproductive health?

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are strongly linked to male reproductive health, mainly through their effects on the development and function of the reproductive tract.

The most common relationship is the development of congenital bilateral absence of the vas deferens (CBAVD), where the sperm transport tubes fail to form properly. This means sperm are produced in the testes but cannot reach the semen, leading to obstructive azoospermia as the main cause of infertility in affected men (Bieniek et al., 2021).

Although many men with CFTR mutations do not have full cystic fibrosis, these genetic changes are still frequently found in men with isolated infertility, particularly those with absent or blocked vas deferens. In these cases, sperm production is usually preserved, but sperm cannot be ejaculated due to the anatomical defect (Bieniek et al., 2021).

There is also evidence that CFTR mutations may have broader effects beyond structural abnormalities. CFTR protein is expressed in parts of the male reproductive system, including the epididymis and sperm, suggesting it may also play a role in sperm maturation and function. As a result, some men may experience additional subtle reductions in sperm quality, although this is less common than obstructive infertility (Bieniek et al., 2021).

Importantly, fertility can often still be achieved in these men through surgical sperm retrieval techniques, such as testicular sperm extraction (TESE) or microsurgical epididymal sperm aspiration (MESA). These procedures allow sperm to be directly collected from the testes or epididymis, bypassing the absent or blocked vas deferens. The retrieved sperm can then be used with assisted reproductive techniques such as intracytoplasmic sperm injection (ICSI) to achieve fertilisation (Bieniek et al., 2021).

Overall, CFTR gene mutations primarily affect male fertility by disrupting the development of the vas deferens, leading to obstructive azoospermia, while in some cases they may also contribute to impaired sperm function.

Bieniek JM, Lapin CD, Jarvi KA. Genetics of CFTR and male infertility. Transl Androl Urol. 2021 Mar;10(3):1391-1400. doi: 10.21037/tau.2020.04.05. PMID: 33850775; PMCID: PMC8039587.

How can genetic counselling support couples facing fertility challenges?

Genetic counselling plays a vital role in supporting couples who face fertility challenges by providing them with both medical guidance and emotional support. Couples undergoing fertility evaluation often encounter complex decisions, particularly when there is a known risk of genetic disorders. Genetic counselling helps these couples understand the nature and inheritance patterns of potential genetic conditions, the associated reproductive risks, and the likelihood of passing these conditions on to their offspring. By providing clear and individualized information, counselling empowers couples to make informed decisions about their reproductive journey and helps reduce anxiety related to uncertainty or misinformation.

For couples at risk of transmitting a genetic condition, one of the key interventions discussed during counselling is in vitro fertilization (IVF) combined with preimplantation genetic testing (PGT). PGT enables embryos created via IVF to be screened for specific genetic mutations or chromosomal abnormalities before implantation. This process allows couples to select embryos that are free from the targeted genetic condition, thereby reducing the risk of having a child affected by the disorder. Different types of PGT exist depending on the nature of the genetic risk: PGT for monogenic disorders (PGT-M) focuses on single-gene mutations, while PGT for aneuploidy (PGT-A) screens for chromosomal abnormalities that can affect fertility or increase miscarriage risk (Fernandes et al., 2024).

Genetic counselling is also essential for individuals who face infertility due to genetic factors that impair their ability to produce gametes or sustain a pregnancy. Chromosomal anomalies, such as Turner syndrome in women and Klinefelter syndrome in men, can lead to ovarian or testicular dysfunction, significantly reducing fertility potential (Sullivan et al., 2014). In addition, single-gene disorders that disrupt hormone function, gamete development, or reproductive tract formation may make natural conception difficult or impossible. Through counselling, patients can gain a clear understanding of how these conditions affect reproductive outcomes, consider options such as donor eggs or sperm, and explore assisted reproductive technologies that may help achieve a successful pregnancy (Zorrilla & Yatsenko, 2013).

Beyond the technical aspects of genetic testing, genetic counselling provides ongoing emotional and psychological support. Couples navigating fertility challenges may experience stress, guilt, or uncertainty, and counselling ensures they have a space to discuss these feelings and receive guidance on coping strategies. It also helps them weigh the benefits and limitations of reproductive technologies, such as IVF and PGT, ethical considerations, and long-term family planning goals. Overall, genetic counselling serves as a comprehensive support system that combines medical expertise with personalized guidance, enhancing both reproductive outcomes and patient well-being (Fernandes et al., 2024).

Zorrilla M, Yatsenko AN. The Genetics of Infertility: Current Status of the Field. Curr Genet Med Rep. 2013 Dec 1;1(4):10.1007/s40142-013-0027-1. doi: 10.1007/s40142-013-0027-1. PMID: 24416713; PMCID: PMC3885174.

Fernandes SLE, de Carvalho FAG. Preimplantation genetic testing: A narrative review. Porto Biomed J. 2024 Jul 11;9(4):262. doi: 10.1097/j.pbj.0000000000000262. PMID: 38993950; PMCID: PMC11236403.

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