De Novo Mutations in Male Infertility

Published: Monday, October 18, 2021, 11:30 a.m. U.S. Eastern Time

Media Contact: Kara Flynn, 202.257.8424,

ROCKVILLE, MD – New research has identified several genes in which de novo mutations – ones that are not present in either parent – may be associated with male infertility. An international team of researchers examined the DNA sequences of 185 infertile males and their unaffected parents, and identified 147 such mutations that could negatively impact male fertility. Miguel Xavier, PhD, a postdoctoral research associate at Newcastle University, presented the results of the study at the American Society of Human Genetics 2021 Annual Meeting.

Infertility is relatively understudied, despite affecting approximately one in seven couples worldwide. By definition, being infertile means not being able to conceive a child, and thus infertility is less likely to be inherited. For this reason, de novo mutations — genetic changes introduced into an individual’s DNA during the formation of reproductive cells or during fertilization when the female and male cells come together and not inherited from either parent — are hypothesized to be involved in many cases.

To investigate this possible role, Dr. Xavier and his colleagues recruited a cohort of 185 infertile males and their unaffected parents. The researchers performed sequencing and identified 147 rare protein-altering de novo mutations in the men that could negatively impact fertility. However, no single gene was affected in more than one individual.

Dr. Xavier and his colleagues then analyzed additional men with unexplained infertility from the International Male Infertility Genomics Consortium. Following an analysis to find mutations with the largest impact on protein function in these additional men, the researchers narrowed the search down to 29 de novo mutations that likely impact male fertility.

Among the new candidate genes identified is RBM5, an essential regulator of sperm cell mRNA maturation. In addition to the individual from the initial cohort carrying the de novo mutation in RBM5, six additional infertile men from the international cohort were found to carry rare mutations in this gene that are likely to prevent RBM5 from working properly.

Dr. Xavier and his colleagues indicated that their results provide the first evidence for a role of de novo mutations in male infertility and have a identified a number of new candidate genes potentially affecting fertility.

“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,” says Dr. Xavier.

“Additionally, 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.”

Media Interest: To learn more about Dr. Xavier’s work or set up an interview, please contact to coordinate.

Reference: Xavier, M., Oud, M.S., Smits, R., Smith, H.E., Mastrorosa, F.K., Holt, G.S., Houston, B.J., de Vries, P.F., Alobaidi, B.K.S., Batty, L.E., Ismail, H., Greenwood, J., Sheth, H., Mikulasova, A., Astuti, G., Gilissen, C., McEleny, K., Turner, H., Coxhead, J., Cockell, S., Braat, D., Fleischer, K., D’Hauwers, K., Schaafsma, E., GEMINI Consortium, Nagirnaja, L., Conrad, D.F., Friedrich, C., Kliesch, S., Aston, K.I., Riera-Escamilla, A., Krausz, C., Gonzaga-Jauregui, C. G., Santibanez-Koref, M.F., Elliott, D.J., Vissers, L.E., Tüttelmann, F., O’Bryan, M., Ramos, L., van der Heijden, G. W., and Veltman, J.A. (October 18, 2021). Abstract: A de novo paradigm for male infertility. Presented at the American Society of Human Genetics 2021 Virtual Meeting.

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