Genetic Causes of Male Infertility: What You Should Know

In short: Genetic causes of infertility are seen more often in men than in women. The best known is Klinefelter syndrome, in which the man has an extra X chromosome. It leads to low testosterone and few sperm, and signs such as undescended testicles may appear in childhood or at puberty.

Is infertility hereditary, or are there other causes behind it? This is a question many couples ask when they are trying to understand why pregnancy hasn’t happened yet.

Infertility is generally defined as the inability to conceive after a full year of regular, unprotected marital relations. In some cases, infertility can have genetic causes, and interestingly, genetic causes of infertility are found more often in men than in women. That said, there are many other possible causes of infertility besides genetic factors, and in some cases, a diagnosis of infertility may be given too soon, before all possible causes have been properly explored.

If you and your partner are struggling to conceive, know that you are not alone, and that understanding the underlying cause is the first step toward finding the right path forward.

The main causes of infertility in men include:

1- Occlusion of the vessels carrying sperm, or testicular injuries and varicocele.

2- Problems with erection and ejaculation.

3- Sperm abnormalities and genetic problems.

4- Hormonal problems and genetic defects.

Besides Klinefelter syndrome, other important genetic causes include microdeletions of the Y chromosome (AZF regions), other chromosomal changes such as translocations, and cystic fibrosis gene (CFTR) mutations, which can cause congenital absence of the vas deferens. Men with no sperm or a very low sperm count (below 5–10 million/mL) are advised to have a karyotype and Y-chromosome microdeletion test, and genetic counselling before ICSI.

Causes of Klinefelter Syndrome

Many families are affected by certain genetic conditions, and one of the most significant genetic causes of infertility is a defect in the chromosomes that carry a person’s genetic traits. The most common of these conditions is known as Klinefelter syndrome. It usually happens by chance, when the egg or the sperm carries an extra X chromosome because of an error in cell division; it is slightly more common with older maternal age, but it can happen at any age.

We look at this topic more closely in our article on male age and sperm quality.

Most men with Klinefelter syndrome have no sperm in the semen (azoospermia), so natural conception is rare. However, sperm can be found in the testis by micro-TESE in about half of cases and used for ICSI, giving many of these men the chance to have their own biological children, especially when treated at a younger age.

In Klinefelter syndrome, a specific genetic difference occurs in men. Typically, a man has one X chromosome and one Y chromosome, but in this syndrome, a man has two X chromosomes and one Y chromosome. There are several variations of this extra X chromosome — about 10–15% of men have a mosaic form (46,XY/47,XXY), where only some cells carry the extra X, and they often have milder features and a better chance of finding sperm. The syndrome is usually not inherited from the parents; it happens by chance.

This syndrome can cause the testicles to develop differently than expected, which may lead to lower testosterone levels and a reduced sperm count, contributing to infertility.

Men with Klinefelter syndrome who wish to have children should not start testosterone injections or gels before seeing a fertility specialist, because testosterone treatment stops sperm production; sperm retrieval and freezing are usually planned first.

One of the options discussed for these men, microsurgical sperm retrieval, has its own detailed article on our site.

Symptoms of Klinefelter Syndrome

Symptoms of this syndrome can appear in early childhood, or they may not become noticeable until puberty. Some men may go through life without realizing they have this condition. In newborn boys, possible early signs include the testicles not descending into the scrotum, or delays in developmental milestones such as sitting, crawling, or talking, or being unusually calm as an infant. It’s important to remember that these signs do not necessarily mean a child has Klinefelter syndrome — a proper medical evaluation is the only way to know for sure.

If you have concerns about male infertility or genetic causes affecting your ability to conceive, the team at

Dr. Najeeb Layyous’s clinic is available to help guide you through appropriate testing and support tailored to your situation.

Dr. Najeeb Layyous F.R.C.O.G

Consultant of Obstetrics and Gynecology and Infertility