A new international study identifies new genetic variants and offers recommendations to improve genomic diagnosis for patients and couples
SOURCE: The Research Institute of the McGill University Health Centre
November 19, 2025
Infertility affects about one in seven couples worldwide, yet for many, the biological cause remains a mystery. In a new study published in Reproductive BioMedicine Online, researchers at The Research Institute of the McGill University Health Centre (The Institute) and international collaborators used advanced genetic sequencing to uncover new mutations that can cause infertility in both men and women. Their findings offer new guidance for how to bring genomic diagnosis into clinical practice.
"Understanding the underlying causes of infertility can transform patient care," said Rima Slim, PhD, Senior Scientist in the Child Health and Human Development Program at The Research Institute of the McGill University Health Centre (The Institute) and senior author of the study. "A precise genetic diagnosis not only helps clinicians tailor treatment options, but also provides patients with clarity and reassurance after years of uncertainty."
Looking inside the genome
The research team examined genomic data and clinical information from nine individuals with unexplained infertility — including women unable to produce mature eggs or embryos, and men whose sperm could not develop normally. Using exome sequencing, a technique that reads the sections of DNA responsible for making proteins, they searched for rare changes that might disrupt reproductive processes.
This approach led the researchers to identify nine rare genetic variants likely linked to infertility across nine different genes — including six that had not been reported previously and a potential new gene associated with male infertility.
"These variants act like small "spelling errors" in the genetic code," says Jalal Vallian Broojeni, a PhD candidate with Prof. Slim. "They are subtle but powerful changes that can prevent key steps in egg or sperm development, fertilization, or early embryo growth."
The power of a diagnosis
Each patient's story highlights the human impact of applying precision medicine to infertility care. One couple, after eight years of infertility and multiple unsuccessful attempts at assisted reproduction, learned that a change in a gene called PLCZ1 was preventing the sperm from triggering normal fertilization — information that opens a path to a specialized treatment protocol.
In another case, a professional woman who sought fertility preservation in her mid-thirties discovered, through genetic testing, a previously undiagnosed hormone disorder that had caused delayed puberty and affected her fertility as an adult. Her story underscores how early, integrated use of precision medicine across the lifespan can change clinical outcomes.
A third patient, who had undergone seven unsuccessful rounds of in vitro fertilization, learned that a genetic change prevented her eggs from completing their normal maturation. With this diagnosis, she was able to make informed decisions about her options and move forward with a clear plan.
"Together, these experiences show how precision medicine can transform patient outcomes — and highlight the need for multidisciplinary collaboration among geneticists, clinicians and reproductive specialists, and genetic counsellors to bring these tools into everyday practice," says Prof. Slim.
Lessons for clinical practice
Supported by the Canadian Institutes of Health Research (CIHR), the study highlights the growing value of genomic diagnosis in infertility evaluation — particularly when standard tests provide no explanation — and notes that testing both partners in some cases and revisiting results as new discoveries emerge can improve diagnostic accuracy and patient care.
"We are still learning just how much the genome can tell us about reproductive health," says Prof. Slim. "By integrating these tools into clinical care, we can move beyond trial and error toward a more personalized approach to fertility care."
About the study
The publication "Lessons learned from the exome sequencing of nine cases of infertility and the way forward" was written by Jalal Vallian Broojeni, Mohamed Elmahdy, Sacha Mitchell, Maryam Rezaei, Ankur Saharan, Ghada Elhady, Sylvia Safwat, Eric Bareke, Ibrahim Abdelrazek, Chengpeng Xu, Lei Li, William Buckett, Asangla Ao, Pierre Miron, Jacek Majewski, Ebtesam Abdalla, and Rima Slim. It was published in Reproductive BioMedicine Online Volume 0, Issue 0, 105359, October 23, 2025 (online ahead of print)
DOI: 10.1016/j.rbmo.2025.105359
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