RAD21L1 – Azoospermia

RAD21L1 (HGNC:16271) has emerged as a candidate gene in the etiology of azoospermia (MONDO_0100459), a condition characterized by the complete absence of sperm in the ejaculate. Several studies have evaluated RAD21L1 in patient cohorts with spermatogenic failure and meiotic arrest, suggesting that genetic variants in this gene may increase the risk for male infertility (PMID:28635411).

In a Japanese cohort, coding single-nucleotide polymorphisms in RAD21L1 were found at significantly higher frequencies in patients with meiotic arrest and Sertoli cell-only syndrome compared to controls, supporting a role for the gene in the pathogenesis of azoospermia (PMID:28635411). This study provided statistical evidence based on 38 affected individuals, strengthening the association between RAD21L1 and the disease.

A subsequent exome analysis performed on 147 patients with spermatogenic arrest further underscored the involvement of RAD21L1 in azoospermia. Although the study evaluated multiple candidate genes, RAD21L1 emerged as one of the genes with supportive data, notably when validated by mouse knockout models that exhibit meiotic arrest and consequent azoospermia (PMID:32741963).

Despite the robust association from case–control and exome studies, no definitive pathogenic coding variant meeting strict HGVS criteria (i.e., a variant described as a complete coding alteration such as a c. change with corresponding (p…) annotation) has yet been reported for RAD21L1. The current genetic evidence is thus derived largely from association studies rather than variant-level segregation data.

Functional evidence strongly supports the role of RAD21L1 in male fertility. Animal models, specifically mouse knockouts, demonstrate that loss of RAD21L1 leads to meiotic arrest and azoospermia, which is concordant with the phenotype observed in human patients (PMID:28635411). These results emphasize the gene’s critical role in ensuring proper meiotic progression and spermatogenesis.

In conclusion, the integration of genetic association data and functional studies provides a coherent narrative that supports a strong association between RAD21L1 and azoospermia. Although additional work is needed to pinpoint definitive pathogenic variants, the current evidence has significant diagnostic utility and may inform future clinical management and gene panel designs for the evaluation of male infertility.

References

• Human fertility (Cambridge, England) • 2017 • Single-nucleotide polymorphisms in the human RAD21L gene may be a genetic risk factor for azoospermia PMID:28635411
• Genetics in Medicine • 2020 • Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men PMID:32741963

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