The Genetics of Infertility: Causes, Choices and Treatments

The latest event from PET (the Progress Educational Trust) – 'The Genetics of Infertility: Causes, Choices and Treatments' – proved a fruitful discussion forum for our assembled clinicians and basic researchers tackling the challenge of unexplained infertility.

Genetic contributions to infertility can seem unintuitive, given that having children, and thereby passing on genes, is itself a measure of fertility. However, a child's genome differs from their parents through new genetic mutations that arise in the sperm, egg or early embryo. New variants linked to male infertility can be inherited through the mother's DNA, and vice versa, and novel combinations of genetic variants may be brought together in a new generation.

Infertility can therefore very much depend on a person's genetics, with speakers at PET's event discussing estimates that genetic factors could account for a substantial proportion of infertility, including previously unexplained cases. The identification of these genetic variants, and the prognosis they can offer, is an active area of clinical research.

Professor Willem Verpoest, professor of reproductive medicine at Utrecht University Medical Centre, the Netherlands, was the first speaker. He opened with a consideration of genetic testing across the scales from chromosomal abnormalities (detectable by microscopy) to the use of sequencing to detect variants affecting single genes.

The best characterised variant of the FMR1 gene is currently included in diagnostic testing for primary ovarian insufficiency (POI), but research is expanding the list of potentially relevant variants to the scale of hundreds of genes. Inclusion of these genes in diagnostic panels can increase diagnostic yield, but also carries the risk of identifying genetic variants of uncertain significance that can be difficult to interpret in the clinic (an important challenge raised by an audience member during the discussion).

Studies of more extensive genetic testing in POI, for example, have shown that adding gene panels and exome sequencing can substantially increase the proportion of patients for whom a potential cause is identified, although this does not mean that every identified variant is causative.

Next was Professor Stéphane Viville, founder of the Genetics of Infertility Unit at the University Hospitals of Strasbourg, France. He spoke about the classification of such variants in a 2023 systematic review of the scientific literature, which identified 395 genes and assessed 466 gene-disease relationships associated with female infertility and differences in sex development. Of these, 105 genes had at least moderate evidence for an association with female infertility.

Such classification depends on clinical case studies, and he highlighted the European Society of Human Reproduction and Embryology's data-sharing Female Reproductive Genetics Initiative, through which researchers are encouraged to share genetic variants of interest.

The third speaker, Professor Joris Veltman, director of the Institute of Genetics and Cancer in Edinburgh, highlighted the equivalent for male infertility – the International Male Infertility Genomics Consortium. Given that these novel variants are rare in the population, Professor Veltman stressed how data sharing is considered crucial both for finding candidates and for excluding false positives in this research phase. This is essential for determining which variants will be useful for future diagnoses in fertility clinics.

Professor Veltman also presented his work tracking the success of testicular sperm extraction as correlated with genetic variants in the patients, although again the small number of patients currently means that this cannot yet be used as an effective diagnostic tool in the clinic.

Several speakers emphasised the unique nature of genetic test results, as findings in one individual can have implications for their relatives. Professor Viville described one case in which a 38-year-old woman with POI was found to carry a variant in the BMP15 gene considered a candidate genetic cause. The woman's 32-year-old sister was recommended to undertake hormonal and genetic testing, which showed a shared genetic variant (jointly inherited from their father) and a reduced ovarian reserve. Fertility preservation by oocyte cryopreservation was recommended for the younger sister, indicating how diagnoses can influence treatment at the level of the family.

The final speaker, Professor Micheline Misrahi – emeritus professor of biochemistry and molecular biology at Paris-Saclay faculty of medicine, France – discussed the utility of linking genetic variants to their effect at particular stages of oocyte maturation. Genetics can guide the choice of intervention: for example, if the affected gene has a molecular function before or after establishment of the ovarian reserve.

More broadly, a specific genetic diagnosis for infertility can also highlight other future health issues that have been associated with the same variant in other patients. For example, Professor Veltman explained that Klinefelter syndrome, a chromosome-based diagnosis of male infertility, is also associated with other health conditions, including an increased risk of osteoporosis.

However, in the context of population screening for such variants, Professor Misrahi was clear in highlighting diagnostic guidelines for POI, for which genetic testing is considered in context with symptoms, patient history (particularly cancer treatments) and autoimmunity testing. She explained that two individuals with the same genetic variant can have different fertility outcomes, as genetic variants are not necessarily completely predictive of infertility.

Professor Viville was keen to highlight that we are operating at the boundary of research and diagnostic testing, and that the data is not yet there for informing carrier screening for infertility. The ethical challenges of expanding carrier screening for genetic variants were the topic of a previous PET discussion (see BioNews 1320 and 1322) and are being addressed by the PRECAS project in partnership with PET.

A group consensus was further reached that polygenic risk scores currently lack sufficient utility at an individual level to predict infertility (for more discussion of polygenic risk scores see BioNews 1320 and 1328).

Where genetic sequencing is used in diagnostics, this is typically through exome sequencing, which focuses on genes (approximately 1.5 percent of the entire human genome). Professor Veltman suggested that current, successful diagnoses are typically covered by these exonic variants, while

Professor Viville indicated that future improvements in genetic diagnosis may increasingly come from widespread use of whole-genome sequencing. Further, the reduced cost of sequencing over time may streamline diagnostics, such that a single sequencing run will provide the same information in a single test, replacing the current independent approaches for chromosomal abnormalities and sequence variants.

To conclude the discussion, Professor Verpoest emphasised the importance of delivering the benefits of genetics research into the clinic to improve diagnostics and provide the best possible care. Professor Veltman drew comparisons with the transformative impact that genome sequencing has provided for personalised cancer treatment, arguing that inclusion of genome sequencing into routine healthcare could guide future infertility diagnoses.

It was clear from the discussion that finding the causative genetic variants for infertility is an active area of research with collaboration between fertility clinics and researchers. Genetic findings are already contributing to infertility diagnoses in the clinic and are likely to play an expanded role in years to come.

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PET is grateful to the Association of Reproductive and Clinical Scientists, the British Fertility Society, Esco Medical, Allwin Medical Devices and Gedeon Richter for supporting this event.

Register for these upcoming PET events:

• The Marcus Pembrey BioNews Writing Prize 2026, taking place in central London on the evening of Wednesday 7 October 2026 – register here.
• Under the Influence: Fertility, Advertising and Social Media, taking place online on Wednesday 4 November 2026 – register here.
• AI and Automation in Fertility and Genomics: Pipeline? Or Pipe Dream?, the PET Annual Conference, taking place in central London on Wednesday 9 December 2026 – register here.