Lack of evidence for genetic defects in previously implicated gene in patients with male infertility

Critical evaluation of published evidence is of paramount importance to prevent incorrect and misleading conclusions on the involvement of genes in diseases. In a letter to Cell, published on April 15^th, ​researchers from the department of Human Genetics at Radboudumc have raised concerns about the claimed role of PIWIL1 D-box region mutations in human male infertility in an earlier publication in Cell.

Infertility is a common condition that affects approximately 10-15% of all couples. About half of the cases can be assigned to male factors. Severe forms of infertility, such as azoospermia (no sperm in the ejaculate) often have a genetic cause. With the introduction of novel sequencing technologies, the number of genetic diagnoses reported for male infertility has grown tremendously.

As shown in an earlier publication by researchers at the Radboudumc, there is a great variability in the evidence for the role of published genetic variants linked to male infertility. Manon Oud and colleagues took a closer look at the presented evidence of all reported male infertility genes to understand which genes are clearly important in the disease etiology and can be used for diagnostic tests. This analysis revealed potential issues with the evidence presented for the involvement of Piwi Like RNA-Mediated Gene Silencing 1 (PIWIL1; also known as HIWI) in human male infertility.

In their letter, Oud et al. point at questionable patterns in the genetic data presented in the original Cell paper. Almost four years since this high impact publication, no other group reported a replication of these findings. Researchers at the Radboudumc, in collaboration with groups in a.o. Germany, the US and Australia which are part of the International Male Infertility Genomics Consortium, were unable to replicate these initial findings a in a combined cohort of 2,740 patients. While that does not exclude a potential role for this gene in the condition, it is clear that PIWIL1 is not a frequently mutated male infertility gene as previously suggested. This is very important to consider before incorporating PIWIL1 into the diagnostic work-up of infertile men.

Joris Veltman, senior author on the paper: “This story underscores the importance of critical evaluation of evidence for previously implicated variants and demonstrates the power of collaborative efforts to establish larger cohorts to validate/better estimate the role of genes in genetic disorders such as male infertility.”