Brigham investigators found that abnormalities in a gene called SYCP2 were associated with low sperm count.

In a discovery 20 years in the making, Brigham investigators have uncovered a genetic abnormality that may be responsible for some unexplained cases of male infertility.

At least one in five cases of infertility remain unexplained. While men’s biology contributes to about half of these cases, doctors are often unable to identify a specific cause of their infertility. Researchers estimate that genetics could explain up to 50 percent of these cases, but many of the genes involved in male infertility remain unknown.

Now, Brigham investigators have found a chromosome rearrangement — a type of genetic mutation that alters DNA structure — and loss-of-function variants affecting one of those genes. Changes affecting this gene, known as SYCP2, are associated with low sperm count. The team’s findings, which report the first cases implicating this gene in four men with infertility, were recently published in the American Journal of Human Genetics.

“We hope that our evidence will contribute to this gene being included in panels for diagnosis of male infertility,” said medical geneticist and corresponding author Cynthia Morton, PhD, of the Department of Obstetrics and Gynecology and the Department of Pathology. “Infertility is a big problem for young people, and 40 to 72 percent of men lack a diagnosis. This means that we have a lot of gene-finding to do. My lab has a longstanding interest in studying individuals who have a balanced chromosome rearrangement where two chromosome segments swap places. In this case, it led us to an important discovery.”

The work that would lead the team to SYCP2 began in 1999, when Morton launched the Developmental Genome Anatomy Project (DGAP) to understand the genetic basis of birth defects and underlying molecular basis of development.

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It was through this initiative that Morton and former graduate student and first author Samantha Schilit, PhD, along with colleagues from Harvard Medical School and Wesleyan University, were referred a case involving a 28-year-old man with a two-year history of infertility and severely low sperm count. By analyzing his chromosomes, the team found a genetic abnormality that led to a 20-fold rise in SYCP2 activity.

Through a series of elegant experiments involving yeast and cellular models, the researchers went about analyzing the effects of this abnormality, finding that it led to defects in sperm cell division — resulting in problems with sperm production and severely low sperm count.

“Balanced chromosomal rearrangements in infertile men are rarely followed up beyond reporting a risk for recurrent miscarriage. This work shows that a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility, and therefore should be considered,” said Schilit.

In addition, the researchers looked for other cases of SYCP2 contributing to male infertility. To do so, they collaborated with investigators at the University of Münster in Germany who had enrolled men with infertility in a separate study. The University of Münster team’s search revealed three men with mutations that disrupt the function of SYCP2. These disruptions in SYCP2 were far more frequent among men with infertility than in the general population.

Morton notes that while the discoveries about SYCP2 may help inform a diagnosis, researchers still have much to learn about what it means for potential infertility treatments.

“A diagnosis can be therapeutic in itself — even if there isn’t something that can be done to correct it. It ends the search for the underlying issue and opens the door for enrolling in clinical trials,” said Morton. “And I believe there is good reason to be optimistic; we now have better tools for discovery and can begin on the path toward therapy.”