Infertility affects millions of couples worldwide. Around 17% of couples experience fertility issues, and in approximately one-third of the cases, the cause lies with the male partner. Male infertility is a complex condition, and in many cases the underlying reason remains unclear.
According to clinical embryologist Liliana Ramos, head of the fertility laboratory at Radboudumc, rapid progress in genetics is beginning to change this picture. Recent collaborative studies with researchers at the department of Human Genetics are providing clearer insights into the underlying genetic causes of male infertility which is reshaping research, clinical diagnostics, and treatment options. Since December 2025, Radboudumc has been officially recognized as a Center of Expertise for male infertility.
For years, genetic testing for male infertility focused on extreme cases where sperm cells were completely absent. The testing looked for chromosomal abnormalities, deletions on the Y chromosome, or variants in the CFTR gene. If these tests yielded negative results or patients displayed other sperm abnormalities, the patients were left without an explanation, even though a genetic cause was still suspected.
Liliana and her colleagues at the Human Genetics department investigated whether exome sequencing, which analyzes all the protein-coding regions of the genome, could replace this limited approach. In a study of 292 men over a ten-month period, exome sequencing revealed a genetic cause of the male infertility in 22.9% of cases, nearly doubling the diagnostic yield of traditional testing. About half of the findings aligned with what existing methods could detect, while the other half involved potential causes that would otherwise have gone unnoticed. While additional tests remain necessary for certain chromosomal findings, exome sequencing is now considered a comprehensive, reliable, first-tier method to detect the genetic causes of male infertility. A genetic diagnosis helps doctors to advise patients about treatment options, possible associated health risks, and family planning.
Spontaneous variants as an underrecognized cause of male infertility
A second study explored the role of de novo variants: genetic changes that are not inherited from either parent but arise spontaneously during egg or sperm formation, or shortly after fertilization. By comparing the DNA of 185 infertile men with those of their unaffected parents, the researchers identified protein-altering, de novo variants that may explain the male infertility. The researchers identified an enrichment of these damaging variants in genes normally intolerant to such changes.
One important finding involved RBM5, a gene essential for sperm development and previously linked to male infertility in mice. In a follow-up study involving over 2,500 infertile men, six deleterious RBM5 variants were found, compared with none in almost 5,800 fertile men. These results suggest that de novo variants play a significant role in severe male infertility.
Clarifying which genes truly matter for diagnostic screening
As genetic research expands, so do the number of genes linked to male infertility. To distinguish genes with stronger evidence from weaker claims, researchers from Radboudumc contributed to a systematic review of genes associated with male infertility. From more than 1,300 publications, they identified 487 genes with varying levels of evidence. In total, 78 genes were confidently linked to male infertility. This work helps laboratories to design accurate diagnostic panels based on the available evidence. Since the number of publications describing genes related to fertility issues continues to rise, diagnostic panels are constantly updated based on the criteria described in this study. More importantly, more patients are receiving genetic testing and results that are clinically meaningful.
A field moving forward
Together, these studies demonstrate that male infertility is shaped by a broader and more complex set of genetic factors than previously recognized. Exome sequencing can increase the diagnostic yield, de novo variants offer new insights into severe cases, and standardized gene evaluations refine which genetic findings are truly important. As these approaches continue to evolve, they offer patients clearer explanations and more personalized guidance for reproductive care.
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Video and article by Lara Holtes (PhD candidate @ Dep. Human Genetics)
Jr. editor for Radboudumc Research Institute for Medical Innovation
