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Sequencing Study Links X Chromosome Genes to Male Infertility

NEW YORK – An international team led by investigators in Spain, Germany, and Italy has tracked down dozens of X chromosome genes that appear to contribute to infertility in men producing little or no sperm.

"Our analysis represents a substantial step toward reducing the gap in our understanding of X-linked genetic causes of spermatogenic failure," senior and corresponding author Csilla Krausz, a researcher at the University of Florence, and her colleagues wrote in the American Journal of Human Genetics on Friday.

Using targeted X chromosome sequencing or exome sequencing, the researchers searched for genetic contributors to infertility in more than 2,350 men with idiopathic forms of non-obstructive azoospermia or cryptozoospermia that could not be explained using conventional diagnostic methods. The participants did not include men with known genetic conditions, environmental exposures, or prior treatments that could explain their lack of sperm production.

"Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored," the authors reported, adding that "most of the independently-acquired X chromosome genes show high expression in the testis and little to no expression in other tissues, implying a specialized role in male reproductive fitness."

By comparing X chromosome sequences from the infertile men, enrolled in four prior studies, to those from men with normal sperm production and sequence data from the gnomAD database, the team tracked down nearly 2,100 rare variants predicted to be pathogenic that were specific to the infertile individuals.

Along with genes previously suspected of contributing to infertility, the researchers flagged hundreds of X chromosome genes that were recurrently mutated in men with infertility. When they whittled that set down by considering associations within and across cohorts, they identified 21 genes with the strongest spermatogenic ties and another 34 genes with more modest associations.

The analyses also led to dozens of likely pathogenic variants or variants of uncertain significance in genes implicated in infertility in the past.

When the team took the most pronounced infertility associations forward for targeted sequence analyses in another 265 men with non-obstructive azoospermia/cryptozoospermia and 54 non-obstructive azoospermia patients, it identified nine infertile men carrying variants in half a dozen of the genes. Still other genes in the candidate set had weaker links to infertility across the replication cohort.

The researchers went on to further validate suspected associations, explore protein interaction profiles for candidate infertility contributors, and search for other genes that had higher-than-usual mutation burdens in infertile men compared with their fertile counterparts.

They also performed a series of follow-up functional experiments in a Drosophila fruit fly model, focusing on the effects of mutations in a gene called RBBP7, which had the highest mutation frequency in the azoospermia/cryptozoospermia-affected men.

"Collectively," the authors suggested, "our study represents a significant step towards the definition of the missing genetic etiology in idiopathic severe spermatogenic failure and significantly reduces the knowledge gap of X-linked genetic causes of azoospermia contributing to the development of future diagnostic gene panels."