Five to ten percent of men find it difficult to conceive a child. For many, the cause is primary testicular disease, or primary spermatogenic failure (SPGF). While genetic factors are considered a key cause, clinical guidelines only recommend testing for chromosomal abnormalities, Y chromosome microdeletions, and variants of the CFTR gene, linked to obstructive azoospermia. This leaves more than half of SPGF cases unexplained, hindering timely infertility management.
Research utilizing whole-exome sequencing (WES) on groups of men with infertility has identified numerous potential genes and variants associated with SPGF. However, the benefits of these findings for enhancing patient care and clinical decision-making are yet to be determined. A study published in The American Journal of Human Genetics sought to gather more generalizable conclusions to assess their applicability and significance in clinical practice. To this end, the researchers screened likely pathogenic (LP) and pathogenic (P) variants in 486 male infertility candidate genes using WES data for 844 Estonian men: 521 with idiopathic SPGF and 323 fertile men with normal sperm. The study is one of the largest on the monogenic causes of male infertility.
Key Findings
A molecular diagnosis was reached for 12% of SPGF cases, with findings in 39 genes. There were no significant differences between men with azoospermia, oligozoospermia, and primary cryptorchidism with SPGF. Out of the 64 genetic variants identified, 30% were found repeatedly in this study or in others on male infertility. The NR5A1 gene was the most commonly affected, with variants identified in six men with SPGF and two men with normal sperm production. The study also confirmed the link between SPGF and newly suggested genes, including ACTRT1, ASZ1, GLUD2, GREB1L, LEO1, RBM5, ROS1, and TGIF2LY. Interestingly, changes in the BNC1 gene, previously linked to female infertility, were identified as potential causes of severely low sperm counts in men.
The findings also suggest that some infertile men might have congenital conditions that affect the development and function of their reproductive systems. Over 30% of the identified variants impacted genes involved in the hormonal system that controls reproduction.
Perhaps more notably, the study revealed that men with genetic infertility were four times as likely to develop cancer compared to the general male population.
These results have already been incorporated into clinical practice in the Andrology Clinic of Tartu University Hospital, with a molecular diagnostic test based on the male infertility gene panel being offered to all patients with appropriate medical indications. This allows for more personalized treatment through quick detection of DNA defects in hundreds of genes associated with spermatogenic failure.
Key Takeaway
Studies continue to show a clear link between genetic factors and male infertility, and in this case, primary spermatogenic failure. This study’s findings highlight the importance of expanding genetic testing beyond current clinical guidelines, to offer more accurate diagnoses and personalized treatment options for infertile men. Integrating genetic insights into clinical practice can enhance the management of infertility, improving outcomes through more tailored treatment approaches.
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