Improved genetic testing strategy doubles the diagnostic yield in male infertility

Male infertility affects 7% of men globally, with 60-70% of all cases undiagnosed – a frustrating challenge for both patients and healthcare providers. For over 25 years, a combination of three genetic techniques was successful in uncovering the most common genetic causes (Y chromosome microdeletions, Klinefelter syndrome, and DNA sequence variants in the CFTR gene).

However, the diagnostic yield has remained unchanged over these years, despite an ongoing surge in knowledge about genetic causes of male infertility. In the past decade, novel sequencing technologies have finally started to shed light on the damaging effect of variants in hundreds of genes involved in male infertility. Examining these genes for pathogenic variants could significantly improve the diagnostic yield of genetic testing, but had not yet found its way to routine diagnostics in the vast majority of laboratories due to cost-efficiency concerns.

Researchers Manon Oud and Dineke Westra from the department of Human Genetics, together with colleagues of the department of Urology and the department of Obstetrics and Gynaecology, developed a test based on exome sequencing, in which all protein-coding regions of the genome are sequenced. By applying a male infertility gene filter to this data, they were able to uncover not only the well-known common causes of male infertility, but also variants in novel genes. Because the test can largely replace the current methods, it is more cost-efficient. An additional benefit of this new test is its suitability for diagnosing other types of male infertility, for which no genetic tests were previously available. The results were published in Andrology on 24 August 2024.

Conducted in two phases, the study first validated the reliability of exome sequencing by testing DNA from patients with known genetic causes, such as Y chromosome microdeletions. The exome sequencing method accurately detected all previously identified anomalies. In the subsequent evaluation study, the researchers analyzed 292 clinical exomes from men struggling with infertility. Exome sequencing identified clinically relevant genetic anomalies in 22.9% of cases, nearly doubling the diagnostic yield compared to current methods. While 10.2% of these cases could have been detected using existing combination of techniques, the additional findings—9.6% excluding cystic fibrosis carriers—demonstrate the enhanced ability to uncover more genetic causes using exome sequencing.

This advancement revolutionizes genetic diagnostics for male infertility, providing more accurate information that can guide treatment, assess potential co-morbidities, and inform risks for future offspring and family members. Although, for the time being, traditional karyotyping will still be necessary for detecting certain chromosomal anomalies, exome sequencing is now implemented as a first-tier genetic test for male infertility in the Radboudumc.

Male Infertility Expertise Center

This genetic test is part of the Male Infertility Expertise Center of the Radboudumc, which is the largest center in the Netherlands in the field of male infertility, with the highest rates of successful pregnancies after an ICSI with surgically retrieved sperm (Society for Obstetrics and Gynecology). The expertise center for male infertility covers the entire chain of care, from research, diagnostics and treatment, up to counseling and follow-up.

Read the study here:

Oud MS, de Leeuw N, Smeets DFCM, Ramos L, van der Heijden GW, Timmermans RGJ, van de Vorst M, Hofste T, Kempers MJE, Stokman MF, D'Hauwers KWM, Faas BHW, Westra D. Innovative all-in-one exome sequencing strategy for diagnostic genetic testing in male infertility: Validation and 10-month experience. Andrology. 2024 Aug 24. doi: 10.1111/andr.13742. Epub ahead of print. PMID: 39180390