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De Novo Mutations Linked to Male Infertility in Trio Exome Sequencing Study

NEW YORK – De novo mutations affecting more than two dozen candidate genes appear to contribute to forms of male infertility caused by very low sperm counts or absence of sperm, according to new research presented this week at the American Society of Human Genetics annual meeting, held virtually this year.

For their study, investigators in the UK, the Netherlands, Australia, Germany, and elsewhere sequenced the exomes of 185 men with unexplained forms of severe oligozoospermia (far lower-than-usual sperm counts) or azoospermia (sperm-free ejaculate), comparing their protein-coding sequences to those of their unaffected parents. They also tapped into data for participants from the International Male Infertility Genomics Consortium.

"Traditionally, male infertility has been investigated under a recessive model of inheritance, but following this method, a large proportion of cases remain unexplained," Miguel Xavier, a postdoctoral research associate at the Newcastle University Biosciences Institute, noted during a poster preview presentation at the conference on Monday.

With that in mind, the team searched for de novo mutations in the infertile male participants that had not been inherited from either unaffected parent, reasoning that infertility and conditions with related symptoms such as Klinefelter syndrome have previously been linked to chromosome-level de novo alterations.

In the process, the investigators flagged 192 rare de novo mutations in the affected men — a set that they subsequently whittled down to 29 candidate mutations based on predicted mutation severity and functional effects.

These included 21 missense mutations, four frameshift changes, a handful of in-frame insertions or deletions, and one premature stop mutation, Xavier reported, noting that suspicious de novo mutations were overrepresented in RBM5 and other genes from messenger RNA maturation or splicing pathways that are typically expressed in the testes during sperm production.

"No other genetic abnormalities were found in these patients, which seems to indicate that the de novo mutations are the genetic cause for the infertility of these men," he added, noting that these mutations appear to exert a dominant effect on infertility.

In an abstract accompanying the presentation, he and his co-authors noted that RBM5 mutations were significantly more common in another group of more than 2,500 infertility cases than in a group of nearly 5,800 fertile male controls. The team also saw higher-than-anticipated representation of de novo mutations in genes that are considered loss-of-function intolerant and in genes coding for interaction-heavy proteins.

Xavier cautioned that additional research is needed to tally the potential de novo contributors to infertility in larger participant groups from different populations, and to validate candidate genes uncovered so far. Even so, he said, results so far point to the possibility of identifying infertility culprits, or diagnosing patients, with the help of exome or genome sequencing.

"By expanding our knowledge of the causes of male infertility, we can not only provide a concrete answer to the individuals affected, but also help clinicians to better advise these patients on the best course of action to take in order to conceive," Xavier said in a statement, adding that "we hope that in the near future we are able to identify more genetic causes of infertility and start developing the means to overcome infertility in these patients. But first, we need to better understand the basics of sperm development and the genetic factors that disrupt it."

The team has provided additional details on the work in a paper under review at a scientific journal, and in a BioRxiv preprint out in February.

The study backs up similar results by others. In a pilot study published online in the journal Andrology in September 2020, an independent team from Slovenia, Macedonia, and Serbia described de novo mutations found by sequencing more than a dozen parent-child trios involving patients with idiopathic azoospermia and another 16 singleton males with the condition.

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