KASH5 – Premature Menopause

This summary describes the association between KASH5 and premature menopause, a condition clinically manifested as premature ovarian insufficiency, primary amenorrhea, and secondary amenorrhea. The available evidence underscores the gene’s role in ovarian function with reports linking homozygous variants with meiotic defects. Multiple lines of genetic and experimental data converge to support the association, making this an important candidate for diagnostic screening in affected women (PMID:35708642). The data have been accrued from both focused case reports and large multi‐patient studies, enhancing the clinical relevance of these findings.

In the initial case report, whole‐exome sequencing in a pedigree with 2 affected individuals identified a homozygous splicing variant in KASH5. Segregation analysis in this family provided evidence that the variant co‐segregates with the premature ovarian insufficiency phenotype (PMID:35708642). The identification of this variant in a familial context supports the autosomal recessive inheritance pattern and establishes a direct genotype–phenotype correlation.

Genetic evidence is further bolstered by a recent multi‐patient study that screened over 1,000 cases of premature ovarian insufficiency. Although KASH5 was one among several genes implicated, its recurrent alteration across patient cohorts significantly strengthens the gene–disease association (PMID:36732629). The combined evidence from both studies indicates that rare variants in KASH5 contribute to disease etiology, thereby increasing the overall diagnostic yield when comprehensive genetic panels are employed.

A key variant reported is the splicing site change, described as c.747G>A (p.Ala249=). This variant was identified in a proband and is predicted to disrupt normal messenger RNA splicing, leading to aberrant protein function. Its detection by clinical sequencing platforms provides a molecular marker that can be used to support diagnostic decision‑making and risk assessment in patients with premature ovarian insufficiency.

Functional studies have revealed that this splicing variant disturbs the nuclear membrane localization of KASH5 and impairs its binding to SUN1. Mouse models with analogous disruptions exhibited defective meiotic homolog pairing and accelerated oocyte depletion, which mimics the clinical scenario of premature ovarian insufficiency (PMID:35708642). These experimental findings add a critical layer of evidence by demonstrating that the molecular defects translate into a biological phenotype that is consistent with the human disease presentation.

In conclusion, the integration of genetic, segregation, and functional data indicates a strong association between KASH5 and premature menopause. Despite the presence of additional contributing factors in the broader spectrum of premature ovarian insufficiency, the evidence related to KASH5 exceeds the minimum scoring threshold and confers significant diagnostic value. Key take‑home: KASH5 variants represent a robust biomarker for premature ovarian insufficiency, offering potential improvements in clinical management and therapeutic decision‑making.

References

• The Journal of clinical endocrinology and metabolism • 2022 • Homozygous Variant in KASH5 Causes Premature Ovarian Insufficiency by Disordered Meiotic Homologous Pairing PMID:35708642
• Nature medicine • 2023 • Landscape of pathogenic mutations in premature ovarian insufficiency PMID:36732629

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