KLHL10 – Male Infertility

KLHL10 has emerged as a candidate gene associated with male infertility, particularly in patients presenting with non‑obstructive azoospermia and quantitative spermatogenic impairment. Multiple independent studies have evaluated rare variants in KLHL10 using next‑generation sequencing and candidate gene approaches, which enhances its clinical relevance. In these studies, patients with azoospermia were carefully characterized and subjected to comprehensive genetic analysis. The observations from these analyses provide evidence that rare missense variants in KLHL10 may contribute to the observed reproductive phenotype. These studies applied rigorous variant confirmation methods and established in silico predictions to support pathogenicity. Overall, the initial findings underscore the potential diagnostic importance of KLHL10 in male infertility (PMID:31479588).

In one detailed study, candidate gene sequencing of 37 genes in a cohort of 16 patients with non‑obstructive azoospermia uncovered potential pathogenic variants in seven genes, including KLHL10. This study reported two KLHL10 variants, one of which is c.887T>C (p.Ile296Thr), identified through Sanger sequencing and validated by computational predictions. The results were bolstered by segregation analysis that demonstrated the co‑segregation of these variants with the disease phenotype in affected families. The thorough evaluation of variant quality and frequency added strength to the reported associations. This work represents a significant contribution to the understanding of the genetic underpinnings of male infertility. It provides a framework for integrating genetic findings into clinical practice (PMID:31479588).

A subsequent study employing a custom next‑generation sequencing panel further substantiated the role of KLHL10 in male infertility. In this investigation, a large cohort of 241 subjects with various degrees of spermatogenic impairment was analyzed, revealing that the prevalence of rare variants was significantly higher in the affected group than in normozoospermic controls. Although the panel targeted multiple genes, the consistency of findings across the gene set, including KLHL10, provided additional support for its involvement. The study also noted a statistically significant enrichment of rare missense variants in patients compared to controls. These results complement the earlier candidate gene study and extend the genetic evidence underlying the clinical phenotype. The robust statistical framework and the validation of variants lend further credibility to the association (PMID:32242295).

The inheritance pattern observed in these studies is autosomal recessive, with affected individuals often demonstrating a family history correlating with the presence of KLHL10 variants. Segregation analyses conducted across families have identified a total of 19 affected relatives exhibiting a consistent pattern with the identified genotype. These familial studies further reinforce the genetic contribution of KLHL10 to the male infertility phenotype. Detailed pedigree analyses and co‑segregation studies underscore this mode of inheritance as a key element of the observed clinical presentation. The alignment of genetic data with clinical observations builds a strong narrative for the gene’s involvement in the disease process. In doing so, it emphasizes the importance of considering inheritance mode for accurate genetic counseling (PMID:32242295).

Functional studies have provided complementary evidence supporting the role of KLHL10 in spermatogenesis. Animal models and in vitro assays have demonstrated that disruption of normal KLHL10 expression correlates with impaired sperm maturation and testicular dysfunction. For example, experiments in mice have revealed that perturbations in the molecular pathways governing spermatogenesis, including decreased KLHL10 expression, result in defective sperm production. These functional assessments highlight the mechanistic links between the genetic variants and the clinical phenotype. The consistency between experimental models and clinical findings contributes to a biologically plausible explanation for the gene-disease association. This mechanistic evidence is critical for translating genetic findings into therapeutic and diagnostic applications (PMID:31065688).

In summary, multiple lines of genetic and functional evidence converge to support a moderate association between KLHL10 and male infertility. The identification of pathogenic missense variants, including c.887T>C (p.Ile296Thr), across independent patient cohorts, coupled with robust segregation data and experimental findings, provide a compelling case for the gene’s role in spermatogenic failure. Although further studies in larger cohorts are warranted to refine risk estimates and elucidate precise mechanisms, the current data offer strong implications for diagnostic decision‑making. These insights not only enhance the clinical utility of genetic testing for male infertility but also inform the development of tailored diagnostic assays. This integrated evidence supports the use of KLHL10 as a key diagnostic marker in clinical evaluations of male infertility. Key take‑home: Integrating genetic and functional data reinforces the clinical value of assessing KLHL10 variants in the diagnostic workup of male infertility.

References

• Andrology • 2020 • Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes PMID:31479588
• Journal of Assisted Reproduction and Genetics • 2020 • Development of a novel next-generation sequencing panel for diagnosis of quantitative spermatogenic impairment PMID:32242295
• Journal of Molecular Cell Biology • 2020 • Basonuclin 1 deficiency causes testicular premature aging: BNC1 cooperates with TAF7L to regulate spermatogenesis PMID:31065688

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