Klinefelter syndrome (KS) is characterized by the presence of an extra X chromosome (47, XXY karyotype). In a previous study on 1,039 patients with KS, we reported an absence of Y Chromosome Microdeletions (YCMs). The lack of YCMs in our KS cohort raises an intriguing question. Why would an extra X chromosome seemingly protect against YCMs? Although the underlying mechanism remains elusive, a growing body of evidence from other studies suggests there is a potential connection between X chromosome trisomy and YCMs.
This review offers some important insights and recommendations on genetic screening for male infertility for clinicians. One key finding is that screening for Y chromosome microdeletions is not necessary for men with Klinefelter syndrome, whether they have the classic form or a mosaic version. On the other hand, the review emphasizes that individuals with certain other chromosomal anomalies, such as mosaic monosomy X karyotype and certain inversions, should be referred for AZF deletion screening. This expands on current recommendations and ensures these patients receive appropriate genetic testing to identify potential factors contributing to their infertility.
Notably, the presence of spermatozoa in a man's ejaculate or successful surgical retrieval does not rule out the possibility of AZFb/AZFbc microdeletions. This underlines the importance of considering these specific genetic deletions, even in men who show some evidence of sperm production. The review also highlights that only 1% of men with sperm concentrations between 1-5 million/mL exhibit AZF microdeletions, suggesting that the current testing thresholds for this population may need to be reassessed. Importantly, we emphasize the need to consider haplogroup distribution in Y-DNA research, as population differences can impact the generalizability of findings, flagging the importance of exercising caution when interpreting Y-DNA research and conducting studies within specific demographic groups. Moreover, the wide variability reported in AZF deletion rates (1.3% to 53%) and Y chromosome microdeletions in Klinefelter syndrome (0-67%) suggests significant inconsistencies in current clinical practices. This highlights the need for standardized testing protocols to ensure more consistent and evidence-based approaches to genetic screening for male infertility.
In the final section of this “Beyond the Abstract” commentary, we discuss a concept we learned during this study. There is an implicit belief that the impact factor of the journal where an article is to be published should dictate the stringency of the peer review process. This notion often leads to less rigorous review processes for articles submitted to lower-impact journals. However, this practice can have detrimental consequences. For instance, consider a scenario where a low-impact journal publishes a paper containing a significant error. By coincidence, this article is cited in a review paper that forms part of a widely followed guideline. As a result, the false information gains credibility and is integrated into the guideline, potentially influencing clinical practices and shaping future research directions. In this situation, challenging the guidelines becomes a complex and time-consuming endeavor. Initially, those seeking to correct the error must identify the flawed information and trace it back to its source in the original article. They must then conduct a thorough analysis to demonstrate the error's significance and potential impact. After confirming the error, the real challenge is persuading the scientific community to recognize the mistake and take corrective action. In this way, researchers who question the status quo often encounter skepticism and opposition, especially when challenging widely accepted but incorrect information. Overcoming these challenges requires unwavering persistence, a commitment to truth, and the ability to present compelling evidence. It demands a willingness to engage in constructive dialogue, address concerns, and provide clarifications with patience and understanding. And remember that behind every revolutionary scientific discovery lies a tale of tenacity - a testament to the transformative might of reason and the unyielding quest for truth.
Written by:
- Hamid Kalantari, BSc, MSc, Cytogenetisist, Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran, Iran
- Marjan Sabbaghian, BSc, MSc, PhD, Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, Tehran, Iran