Infertility in some men may be caused by X chromosome mutations

An international study has identified more than 50 genes on the X chromosome in which mutations may cause poor sperm production

By Christa Lesté-Lasserre

An international study has identified more than 50 genes on the X chromosome in which mutations may cause poor sperm production.

Nearly half of all men with low or zero sperm count have no medical explanation for their infertility. In the past few years, studies have identified three X chromosome genes that could be involved in sperm production issues. But Csilla Krausz at the University of Florence in Italy wondered if there might be other genes on the X chromosome that play a role.

Krausz and her colleagues ran genetic analyses on 2354 men with less than 10,000 sperm per millilitre of their semen, then compared the results with those from another 209 men with normal sperm counts of up to 200 million per millilitre. The study did not include transgender or non-binary people. The men came from across Europe and had diverse ages and ethnicities. Before the study, their doctors had found no causes for the low or absent sperm counts of those affected.

The analysis discovered hundreds of mutated genes on the infertile men’s X chromosomes, including the three previously identified in earlier studies. Through further investigation, the researchers honed in on 21 new genes that they considered particularly strong culprits for poor sperm production.

Most of the mutations in these genes affected the way the men’s testicular cells divide to make sperm cells, and the researchers found them repeatedly in these men – as well as in some infertile male flies and mice.

The team also determined another 34 X chromosome genes in which mutations were probably involved in male infertility and should be investigated further.

Because people assigned male at birth inherit one X chromosome from their mother and one Y chromosome from their father, this means that sperm-related infertility could be passed down from mothers to sons, says Krausz. But the mutations might also occur spontaneously during egg or embryo development, she adds.

“People often think about the X chromosome as a female chromosome, because females have two X chromosomes,” she says. “So initially, no one was really thinking that the X chromosome could be so [involved] in male [reproductive] fitness. But [our findings] are fitting with the theory that the X chromosome is important for male reproduction.”

In most cases, the genetic mutations lead to low sperm counts, so it is still possible for these men to have children – usually with medical assistance – and pass on the mutation to their daughters. The daughters would then have a 50/50 chance of passing the mutation on to their sons, depending on which X chromosome they pass on.

“We had cases where we had two brothers,” says Krausz. “One brother was the unlucky one because he got the mutated gene, and the other brother had the good X chromosome, without the mutation.”

With a better understanding of the mutations that cause infertility, doctors might be able to use genetic testing to diagnose the causes of low sperm counts and choose the most appropriate treatments.

Journal reference: The American Journal of Human Genetics , DOI: 10.1016/j.ajhg.2022.06.007

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