Genes play an important role in how your reproductive system develops and works. Sometimes, a change involving a gene or a chromosome can affect your ability to produce sperm or prevent sperm from getting into your semen. If you’re having fertility problems, that doesn’t automatically mean there’s a genetic cause. But in some situations, genetic testing can help explain what’s happening and influence what happens next. The result of genetic testing can matter for more than getting a diagnosis. Some genetic findings affect whether sperm can be retrieved for fertility treatment. Others can affect a couple’s chance of having a child with a genetic condition. Here’s what you need to know about the genetic causes of male infertility and when you need to get tested.
What does a genetic cause of infertility mean?
It means the problem starts with a variation in your DNA. Sometimes that variation is passed down from a parent. Sometimes it happens by chance when sperm or eggs are being made. Either way, you didn’t cause it.
They affect fertility in one of two ways. Some reduce or stop sperm production in the testes. Others leave production working normally but block the route sperm take to get out.
Genetic causes of male infertility include having an unusual number or structure of chromosomes, missing small sections of the Y chromosome, or changes in particular genes.
Three important examples are:
There are many other genes associated with male infertility, but they are very rare. But finding a genetic change is useful clinically when it helps explain the fertility problem or changes decisions about treatment, fertility care or having biological children.
Common genetic causes of male infertility
Klinefelter syndrome
Klinefelter syndrome is the collection of characteristics in males caused by having two or more X chromosomes. Most men have one X and one Y chromosome. Men with Klinefelter syndrome have at least one extra X — the most common variation is 47XXY.
One or two in every 1,000 baby boys has an extra X chromosome, and many men are never diagnosed at all. For some, the first sign of Klinefelter syndrome that is noticed is that they can’t conceive, because most men with the condition make very few sperm or none at all.
Klinefelter syndrome is genetic, but it is not inherited. It happens when the sex chromosomes fail to separate properly as an egg or sperm is being made, and it isn’t passed to your children.
Y chromosome microdeletions
A Y chromosome microdeletion is a small missing piece of the Y chromosome. The missing section sits in an area called the AZF region, which carries the instructions for making sperm. When part of this region is gone, sperm production drops sharply or stops.
Y chromosome microdeletions turn up often among men with very low sperm counts — 5% of men with a sperm concentration below 5 million per millilitre and 10% of men who produce no sperm.
The part that is missing matters. Deletions in the AZFc region often still leave pockets of sperm production in the testes. Complete AZFa or AZFb deletions do not.
Congenital absence of the vas deferens
The vas deferens is the tube that carries sperm out of each testis. Some men are born without it, on one side or both. Sperm production is usually normal, but the sperm have no way out, so none show up in the semen.
This is linked to changes in the CFTR gene, the same gene involved in cystic fibrosis. Carrying a CFTR change doesn’t mean you have cystic fibrosis.
If your vas deferens is missing or abnormal, an imaging scan of your kidneys is also recommended, because the two develop at the same time and a problem in one can point to a problem in the other.
When is genetic testing recommended?
Genetic testing isn’t part of a first fertility check. It comes after a semen analysis shows a problem, and it is targeted rather than routine. Australian guidelines set out when each test should be offered:
If your azoospermia is caused by a blockage, karyotype and Y chromosome microdeletion testing are not routinely offered, because sperm production in that situation is usually normal.
What does a genetic diagnosis mean for having children?
With Klinefelter syndrome, semen analysis and sperm freezing are recommended if there are any sperm in the semen to freeze. If there are none, sperm can sometimes still be found in the testes and used for ICSI, where a single sperm is injected into an egg. Treatment for Klinefelter syndrome involves testosterone replacement therapy and it’s important to discuss family planning before starting it. This is because it shuts sperm production down and is not prescribed to men who want children now or in the near future.
With a Y chromosome microdeletion, any son conceived using your sperm inherits the deletion and carries a high risk of the same fertility problems in adulthood. Telling couples this before ICSI is a required step, not an optional one. Where AZFa or AZFb is completely deleted, surgical sperm retrieval is not attempted, because it doesn’t succeed.
With a CFTR change, sperm can often be collected directly from the testes or epididymis. AN important thing to consider is your partner’s genetics. A child can only inherit cystic fibrosis by receiving a changed copy of the gene from both parents, so testing the female partner and referral to a genetic counsellor are recommended. Medicare has covered carrier screening for cystic fibrosis since November 2023, for people who are pregnant or planning a pregnancy and their reproductive partners.
Where sperm have to be retrieved surgically, micro-TESE is the preferred method, with conventional TESE used if micro-TESE isn’t available near you.
How you might feel about a genetic cause of male infertility
Fertility problems are a considerable source of stress for both partners. A genetic cause adds something specific: it is permanent, it isn’t anyone’s fault, and it can’t be improved by changing things you can control.
Genetic counselling is offered to every couple with an identified genetic abnormality. A genetic counsellor explains what your result means for your health, your chance of having a child, and for any children you do have. Ask for the referral rather than waiting for it to be offered, and ask your GP about counselling for you and your partner.
People also ask
What genetic conditions cause male infertility?
The most common are Klinefelter syndrome, Y chromosome microdeletions and changes to the CFTR gene. The first two reduce or stop sperm production. CFTR changes can leave you without the tube that carries sperm out of the testes. Other chromosome rearrangements found on karyotype testing can also cause infertility or repeated pregnancy loss.
When should I get genetic testing for male infertility?
After a semen analysis shows a problem, not before. Karyotype testing is offered for unexplained azoospermia or a sperm count below 10 million per millilitre of semen. Y chromosome microdeletion testing is offered for sperm counts below 5 million and considered essential below 1 million. CFTR testing is recommended if your vas deferens is missing or abnormal.
Can a man with Klinefelter syndrome father children?
Sometimes, with help. If there are any sperm in your semen, freezing them is recommended. If there are none, a specialist may be able to retrieve sperm from the testes with a microTESE, for use in ICSI. Retrieval doesn’t always succeed, so ask a specialist about your own odds before you decide.
Will my son inherit my fertility problem?
With a Y chromosome microdeletion, yes. Sons conceived with your sperm inherit the deletion and are likely to face fertility problems as adults. With Klinefelter syndrome, no, because the condition isn’t inherited. With a CFTR change, the risk to your children depends on whether your partner carries one too.
